Pharmacology and Molecular Therapeutics Faculty & Staff
Pharmacology and Molecular Therapeutics
PHA Contact Info
Uniformed Services University of the Health Sciences
Department of Pharmacology and Molecular Therapeutics
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-3223
FAX: (301) 295-3220
PHA - Leadership
Regina M Day, Ph.D.
Name: Regina M Day, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Vice Chair
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Email:
Office Phone:
(301) 295-3236
Education
A.B. Smith College, Northampton, MA, USA
Ph.D. Tufts University, Boston, MA, USA
Ph.D. Tufts University, Boston, MA, USA
Irwin Lucki, Ph.D.
Name: Irwin Lucki, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Professor and Chair
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Neuropharmacology
Antidepressant drugs
Email:
Office Phone:
(301) 295-3248
Education
Education: 1972 B.A. University of Illinois, Psychology
1976 M.A. University of Iowa, Psychology
1979 Ph.D. University of Iowa, Biopsychology
Postgraduate Training:
1979-1981 Postdoctoral Research Fellow, Psychopharmacology Training Program, Department of Psychiatry, University of Pennsylvania
1976 M.A. University of Iowa, Psychology
1979 Ph.D. University of Iowa, Biopsychology
Postgraduate Training:
1979-1981 Postdoctoral Research Fellow, Psychopharmacology Training Program, Department of Psychiatry, University of Pennsylvania
Biography
Selected from 180 publications:
Cryan, J.F., Valentino, R.J. and Lucki, I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neuroscience and Biobehavioral Reviews, 2005, 29:547-569.
Valentino, R.J., Lucki, I. and Van Bockstaele, E. Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction. Brain Research, 2010, 1314:29-37. PMC2819581
Ho, N., Sommers, M.S. and Lucki, I. Effects of diabetes on hippocampal neurogenesis: Links to cognition and depression. Neuroscience and Biobehavioral Reviews, 2013, 37:1346-1362. PMC3788092
Browne, C.A. and Lucki, I. Mechanisms mediating the antidepressant-like Lucki, I. The spectrum of behaviors influenced by serotonin. Biological Psychiatry, 1998, 44:151-162.
Page, M.E., Cryan, J.F., Sullivan, A., Dalvi, A. and Lucki, I. Behavioral and neurochemical effects of EMD 68843: A combined selective inhibitor of serotonin reuptake and partial 5-HT1A receptor agonist. Journal of Pharmacology and Experimental Therapeutics, 2002, 302:1-8.
Carr, G.V. and Lucki, I. The role of serotonin receptor subtypes in treating depression: A review of animal studies. Psychopharmacology, 2011, 213:265-287. PMC3374933
Carr, G.V., Schechter, L.E. and Lucki, I. Antidepressant and anxiolytic effects of
selective 5-HT6 receptor agonists in rats. Psychopharmacology, 2011, 213:499-507. PMC2910165
effects of ketamine: Screening for fast-acting novel antidepressants. Frontiers in Neuropharmacology, 2013, 4:161, 1-18. PMC3873522.
Mayorga, A.J., Dalvi, A., Page, M.E., Zimov-Levinson, S., Hen R. and Lucki, I. Antidepressant-like behavioral effects in 5-HT1A and 5-HT1B receptor mutant mice. Journal of Pharmacology and Experimental Therapeutics, 2001, 298:1101-1107.
Cryan, J.F., O’Leary, O.F., Jin, S.-H., Friedland, J.C., Ouyang, M., Hirsch, B.R., Page, M.E., Dalvi, A., Thomas, S.A. and Lucki, I. Norepinephrine deficient mice lack responses to antidepressant drugs, including SSRIs. Proceedings of the National Academy of Sciences, 2004, 101:8186-8191.
O’Leary, O.F., Bechtholt, A.J., Crowley, J.J., Valentino, R.J. and Lucki, I. The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs. European Neuropsychopharmacology, 2007, 17:215-226.
Balu, D.T., Turner, J.R., Brookshire, B.R., Hill, T.E., Blendy, J.A. and Lucki, I. Brain monoamines and responses to antidepressant drugs in MRL/MpJ versus C57BL/6J and mice. Neuropharmacology, 2013, 67:503-510. PMC437180
Cryan, J.F., Markou, A. and Lucki, I. Assessing antidepressant-like activity in laboratory animals: Recent developments and future needs. Trends in Pharmacological Sciences, 2002, 23(5): 238-245.
Crowley, J.J. and Lucki, I. Opportunities to discover genes regulating depression and antidepressant response from rodent behavioral genetics. Current Pharmaceutical Design, 11:157-169, 2005.
Bechtholt, A.J., Valentino, R.J. and Lucki, I. Overlapping and distinct brain regions associated
with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine. Neuropsychopharmacology, 2008, 33:2117-2130.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Price, M. L., Curtis, A.L., Kirby, L.G., Valentino, R.J. and Lucki, I. Biphasic effects of corticotropin-releasing factor on brain serotonergic activity. Neuropsychopharmacology, 1998, 18:492-502.
Price, M.L. and Lucki, I. Regulation of serotonin release in the lateral septum and striatum by corticotropin-releasing factor. Journal of Neuroscience, 2001, 21:2833-2841.
Howard, O., Carr, G.V., Hill, T.E., Valentino, R.J. and Lucki, I. Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin. Psychopharmacology, 2008, 199:569-82. PMC2744742
Snyder, K.P., Hill-Smith, T.E., Lucki, I. and Valentino, R.J. Corticotropin-releasing factor in the rat dorsal raphe nucleus promotes different forms of behavioral flexibility depending on social stress history. Neuropsychopharmacology, 2015, 40:2517-25. PMCID in process.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Falcon, E., Maier, K., Robinson, S.A. and Lucki, I. Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice. Psychopharmacology, 2015, 232:907-915. PMC4326609
Browne, C.A., van Nest, D. and Lucki, I. Antidepressant-like effects of buprenorphine in rats are strain dependent. Behavioural Brain Research, 2015, 278:385-392. PMC4382376
Falcon, E., Browne, C.A., Leon, R.M., Fleites, V.C., Sweeney, R., Kirby, L.G. and Lucki, I. Antidepressant-like effects of buprenorphine are mediated by kappa opioid receptors. Neuropsychopharmacology, 2016, 41(9):2344-2351. PMC4946065
A full bibliography of over 170 peer-reviewed publications is available at: http://www.ncbi.nlm.nih.gov/sites/myncbi/irwin.lucki.1/bibliography/45296221/public/?sort=date&direction=ascending.
Cryan, J.F., Valentino, R.J. and Lucki, I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neuroscience and Biobehavioral Reviews, 2005, 29:547-569.
Valentino, R.J., Lucki, I. and Van Bockstaele, E. Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction. Brain Research, 2010, 1314:29-37. PMC2819581
Ho, N., Sommers, M.S. and Lucki, I. Effects of diabetes on hippocampal neurogenesis: Links to cognition and depression. Neuroscience and Biobehavioral Reviews, 2013, 37:1346-1362. PMC3788092
Browne, C.A. and Lucki, I. Mechanisms mediating the antidepressant-like Lucki, I. The spectrum of behaviors influenced by serotonin. Biological Psychiatry, 1998, 44:151-162.
Page, M.E., Cryan, J.F., Sullivan, A., Dalvi, A. and Lucki, I. Behavioral and neurochemical effects of EMD 68843: A combined selective inhibitor of serotonin reuptake and partial 5-HT1A receptor agonist. Journal of Pharmacology and Experimental Therapeutics, 2002, 302:1-8.
Carr, G.V. and Lucki, I. The role of serotonin receptor subtypes in treating depression: A review of animal studies. Psychopharmacology, 2011, 213:265-287. PMC3374933
Carr, G.V., Schechter, L.E. and Lucki, I. Antidepressant and anxiolytic effects of
selective 5-HT6 receptor agonists in rats. Psychopharmacology, 2011, 213:499-507. PMC2910165
effects of ketamine: Screening for fast-acting novel antidepressants. Frontiers in Neuropharmacology, 2013, 4:161, 1-18. PMC3873522.
Mayorga, A.J., Dalvi, A., Page, M.E., Zimov-Levinson, S., Hen R. and Lucki, I. Antidepressant-like behavioral effects in 5-HT1A and 5-HT1B receptor mutant mice. Journal of Pharmacology and Experimental Therapeutics, 2001, 298:1101-1107.
Cryan, J.F., O’Leary, O.F., Jin, S.-H., Friedland, J.C., Ouyang, M., Hirsch, B.R., Page, M.E., Dalvi, A., Thomas, S.A. and Lucki, I. Norepinephrine deficient mice lack responses to antidepressant drugs, including SSRIs. Proceedings of the National Academy of Sciences, 2004, 101:8186-8191.
O’Leary, O.F., Bechtholt, A.J., Crowley, J.J., Valentino, R.J. and Lucki, I. The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs. European Neuropsychopharmacology, 2007, 17:215-226.
Balu, D.T., Turner, J.R., Brookshire, B.R., Hill, T.E., Blendy, J.A. and Lucki, I. Brain monoamines and responses to antidepressant drugs in MRL/MpJ versus C57BL/6J and mice. Neuropharmacology, 2013, 67:503-510. PMC437180
Cryan, J.F., Markou, A. and Lucki, I. Assessing antidepressant-like activity in laboratory animals: Recent developments and future needs. Trends in Pharmacological Sciences, 2002, 23(5): 238-245.
Crowley, J.J. and Lucki, I. Opportunities to discover genes regulating depression and antidepressant response from rodent behavioral genetics. Current Pharmaceutical Design, 11:157-169, 2005.
Bechtholt, A.J., Valentino, R.J. and Lucki, I. Overlapping and distinct brain regions associated
with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine. Neuropsychopharmacology, 2008, 33:2117-2130.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Price, M. L., Curtis, A.L., Kirby, L.G., Valentino, R.J. and Lucki, I. Biphasic effects of corticotropin-releasing factor on brain serotonergic activity. Neuropsychopharmacology, 1998, 18:492-502.
Price, M.L. and Lucki, I. Regulation of serotonin release in the lateral septum and striatum by corticotropin-releasing factor. Journal of Neuroscience, 2001, 21:2833-2841.
Howard, O., Carr, G.V., Hill, T.E., Valentino, R.J. and Lucki, I. Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin. Psychopharmacology, 2008, 199:569-82. PMC2744742
Snyder, K.P., Hill-Smith, T.E., Lucki, I. and Valentino, R.J. Corticotropin-releasing factor in the rat dorsal raphe nucleus promotes different forms of behavioral flexibility depending on social stress history. Neuropsychopharmacology, 2015, 40:2517-25. PMCID in process.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Falcon, E., Maier, K., Robinson, S.A. and Lucki, I. Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice. Psychopharmacology, 2015, 232:907-915. PMC4326609
Browne, C.A., van Nest, D. and Lucki, I. Antidepressant-like effects of buprenorphine in rats are strain dependent. Behavioural Brain Research, 2015, 278:385-392. PMC4382376
Falcon, E., Browne, C.A., Leon, R.M., Fleites, V.C., Sweeney, R., Kirby, L.G. and Lucki, I. Antidepressant-like effects of buprenorphine are mediated by kappa opioid receptors. Neuropsychopharmacology, 2016, 41(9):2344-2351. PMC4946065
A full bibliography of over 170 peer-reviewed publications is available at: http://www.ncbi.nlm.nih.gov/sites/myncbi/irwin.lucki.1/bibliography/45296221/public/?sort=date&direction=ascending.
Representative publications, projects, and/or deployments
- 2007 - present, Principal Field Editor, Psychopharmacology
- 1995 - present, Editorial Advisory Board, Neuropsychopharmacology
- 2014 – present, Editorial Advisory Board, Neurobiology of Stress
- Buprenorphine for Depression and Anxiety.PI. NIMH, R01 MH92412, 2012-2018. Total direct costs = $1,250,000. The goal of this grant is to examine animal models supporting the development of buprenorphine for the clinical treatment of depression and anxiety.
- Kappa Receptor Antagonists as Rapid Acting Antidepressants. PI. NIMH, R01 MH105623, 2016-2020. Total direct costs = $1,000,000. The goal of this grant is to study animal models supporting the development of novel kappa receptor antagonists for the clinical treatment of mood disorders.
- Training Program in Neuropsychopharmacology. NIMH, T32 MH14654-34-38, 1978-2021. I was Training Program Director at the University of Pennsylvania 1992-2016.
- Regulation of Hippocampal Neurogenesis by Antidepressants. PI. NIMH, R01 MH86599, 2009-2015.
- Biology of Serotonin in Brain; Program Project Grant: Irwin Lucki, Ph.D., Program Director (1994-2007). NIMH, PO1-MH-48125.
- Regulation of Neurogenesis by Stress and Antidepressants. Program Director. National Cooperative Drug Discovery Group involving University of Pennsylvania and Wyeth Neuroscience. U01-MH 72832, 2005-2009.
Bibliography
- 2016- present Professor (with tenure) and Chair, Department of Pharmacology and Molecular Therapeutics, Uniformed University of the Health Sciences, Bethesda MD
- 2016-present Professor, Department of Psychiatry, Uniformed University of the Health Sciences, Bethesda MD
- 1996-2016 Professor of Psychology in Psychiatry (with tenure), Depts. of Psychiatry and Pharmacology, University of Pennsylvania, Philadelphia PA
- 1990-1996 Associate Professor of Psychology in Psychiatry (with tenure), Depts. of Psychiatry and Pharmacology, University of Pennsylvania, Philadelphia PA
- 1989-1990 Assistant Professor, Department of Pharmacology, University of Pennsylvania, Philadelphia PA
- 1984-1990 Assistant Professor of Psychology in Psychiatry, Department of Psychiatry, University of Pennsylvania, Philadelphia PA
- 1981-1984 Research Associate, Department of Psychiatry, University of Pennsylvania, Philadelphia PA
PHA - Neuropharmacology
Brian M. Cox, Ph.D.
Name: Brian M. Cox, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Professor of Pharmacology & Neuroscience
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Neuropharmacology - opiate drugs & substance use disorderds
Traumatic brain injury - mechanisms & biomarkers
Email:
Office Phone:
(301) 295-3260
Education
Ph.D. in Pharmacology, St. Mary's Hospital Medical School, University of London, London, United Kingdom, 1965
B.Sc. in Pharmacolopy, Chelsea College of Science & Technology, University of London, London, United Kingdom, 1962
B.Sc. in Pharmacolopy, Chelsea College of Science & Technology, University of London, London, United Kingdom, 1962
Biography
Dr. Cox is currently Professor of Pharmacology and Neuroscience at the Uniformed Services University (USU) in Bethesda MD. He received his initial training in pharmacology from Chelsea College of Science and Technology in London, UK, and received a Ph.D. in Pharmacology from St. Mary's Hospital Medical School, University of London, UK. After teaching pharmacology to pharmacy and science students at Chelsea College of Science and Technology of the University of London for eight years, he became a visiting scientist in the Department of Pharmacology at Stanford University, and was appointed Consulting Associate Professor of Pharmacology at Stanford in 1978. Concurrently, he served as Laboratory Research Group Director and then Associate Director for Research for the Addiction Research Foundation in Palo Alto, CA. In 1981, Dr. Cox moved to his current position at USU, where he served as chair of the Department of Pharmacology from 1995 until 2007. He currently also serves as an Assistant Dean for Graduate Education at USU.
For most of his career Dr. Cox's research has focused on characterizing the receptors utilized by opiate drugs and their endogenous ligands, and in defining potential physiological and pathophysiological roles for endogenous opioids and other neuropeptides. His lab is currently studying factors affecting peptide and receptor expression, and changes at the cellular level induced by drugs of abuse, severe stress, or neural injury. He now leads the Biomarkers Group of the USU/NIH Center for Neuroscience and Regenerative Medicine, evaluating neurochemical mechanisms underlying traumatic brain injury and potential biomarkers for TBI.
Dr. Cox has been a member of the American Society for Pharmacology and Experimental Therapeutics (ASPET) since 1976. He served as Secretary/Treasurer of (1997-2000), and was elected President of ASPET for 2009-2010. He chaired the ASPET Board of Publications Trustees from 2002-2007. He has served on the Editorial Boards of the Journal of Pharmacology and Experimental Therapeutics (1998 – present), Molecular Pharmacology (1981-1994), and Molecular Interventions (2000-2002). Dr. Cox was a member of the ASPET Scientific Program Committee from 1986-1990 and Chaired the Program Committee from 1990-1996. He served as ASPET’s representative to the Experimental Biology Program Committee from 1991-1994 and served on the Experimental Biology Board from 1996-1999 (as Chairman for 1998-1999). He is currently serving a second term as a member of the Board of Directors of the Federation of American Societies of Experimental Biology.
Dr. Cox was the ASPET representative to the International Advisory Committee for the 1998 International Union of Pharmacology (IUPHAR) Congress in Munich, Germany, and chaired the IUPHAR World Congress of Pharmacology Scientific Program Committee for the 2002 meeting, held in San Francisco, CA. He is also a member of the British Pharmacological Society, the Society for Neuroscience, the AAAS, the American Society for Neurochemistry, and the International Narcotics Research Conference (for which he served as President from 1994-1998).
For most of his career Dr. Cox's research has focused on characterizing the receptors utilized by opiate drugs and their endogenous ligands, and in defining potential physiological and pathophysiological roles for endogenous opioids and other neuropeptides. His lab is currently studying factors affecting peptide and receptor expression, and changes at the cellular level induced by drugs of abuse, severe stress, or neural injury. He now leads the Biomarkers Group of the USU/NIH Center for Neuroscience and Regenerative Medicine, evaluating neurochemical mechanisms underlying traumatic brain injury and potential biomarkers for TBI.
Dr. Cox has been a member of the American Society for Pharmacology and Experimental Therapeutics (ASPET) since 1976. He served as Secretary/Treasurer of (1997-2000), and was elected President of ASPET for 2009-2010. He chaired the ASPET Board of Publications Trustees from 2002-2007. He has served on the Editorial Boards of the Journal of Pharmacology and Experimental Therapeutics (1998 – present), Molecular Pharmacology (1981-1994), and Molecular Interventions (2000-2002). Dr. Cox was a member of the ASPET Scientific Program Committee from 1986-1990 and Chaired the Program Committee from 1990-1996. He served as ASPET’s representative to the Experimental Biology Program Committee from 1991-1994 and served on the Experimental Biology Board from 1996-1999 (as Chairman for 1998-1999). He is currently serving a second term as a member of the Board of Directors of the Federation of American Societies of Experimental Biology.
Dr. Cox was the ASPET representative to the International Advisory Committee for the 1998 International Union of Pharmacology (IUPHAR) Congress in Munich, Germany, and chaired the IUPHAR World Congress of Pharmacology Scientific Program Committee for the 2002 meeting, held in San Francisco, CA. He is also a member of the British Pharmacological Society, the Society for Neuroscience, the AAAS, the American Society for Neurochemistry, and the International Narcotics Research Conference (for which he served as President from 1994-1998).
Representative publications, projects, and/or deployments
- Assistant Dean for Graduate Education, Uniformed Services University, Bethesda MD 20814, since 2014
- Director, Biospecimen Repository, Center for Neuroscience & Regenerative Medicine, Uniformed Services University, Bethesda MD 20814, since 2009
- Professor of Pharmacology, Uniformed Services University, Bethesda MD 20814, since 1981
- Associate Director for Research, Addiction Research Foundation, Stanford, California, 94305, 1977-1981
- Consulting Associate Professor of Pharmacology, Stanford University, Stanford CA, 94305. 1978 - 1981
- Research Associate, Director, Laboratory Research Group, Addiction Research Foundation, Stanford, California, 94305, 1973-1977
- Lecturer (British System) in Pharmacology, Chelsea College, University of London, London, United Kingdom, 1965-1973
- Nicholas Research Fellow, St. Mary's Hospital Medical School, University of London, London, United Kingdom, 1962-1965
Bibliography
- Cox, B.M. and Weinstock, M. Quantitative studies of the antagonism by nalorphine of some of the actions of morphine-like analgesic drugs. Br. J. Pharmac. 22:289-300, 1964.
- Cox, B.M. and Osman, O.H. Inhibition of the development of tolerance to morphine in rats by drugs which inhibit ribonucleic acid or protein synthesis. Br. J. Pharmac. 38:157-170, 1970.
- Cox, B.M., Opheim, K., Teschemacher, H.-J. and Goldstein, A. A peptide-like substance from pituitary that acts like morphine. 2. Purification and properties. Life Sci. 16:1777-1782, 1975.
- Goldstein, A., Cox, B.M., Klee, W.A., and Nirenberg, M. Endorphin from pituitary inhibits cyclic AMP formation in homogenates of neuroblastoma X glioma hybrid cells. Nature 265:362-363, 1977.
- Whitnall, M.H., Gainer, H., Cox, B.M. and Molineaux, C.J. Dynorphin A(1-8) is contained within vasopressin neurosecretory vasicles in rat pituitary. Science 222:1137-1139, 1983.
- Faden, A.I., Molineaux, C.J., Rosenberger, J.G., Jacobs, T.P. and Cox, B.M. Endogenous opioid immunoreactivity in rat spinal cord following traumatic injury. Ann. Neurol. 17:386-390, 1985.
- Werling, L.L., Puttfarcken, P.S. and Cox, B.M. Multiple agonist-affinity states of opioid receptors: regulation of binding by guanyl nucleotides in guinea pig cortical, NG108-15, and 7315c cell membranes. Mol. Pharmacol. 33:423-431, 1988.
- Marti M, Mela F, Fantin M, Zucchini S, Brown JM, Witta J, Di Benedetto M, Buzas B, Reinscheid RK, Salvadori S, Guerrini R, Romualdi P, Candeletti S, Simonato M, Cox BM and Morari M. Blockade of nociceptin/orphanin FQ transmission attenuates symptoms and neurodegeneration associated with Parkinson’s disease. J. Neuroscience 25: 9591-9601, 2005.
- Authement ME, Kodangatil JN, Gouty S, Rusnak M, Symes AJ, Cox BM, Nugent F. Histone deacetylase inhibition rescues maternal deprivation-induced GABAergic metaplasticity through restoration of AKAP signaling. Neuron 86: 1240-1252, 2015.
- Authement M, Kassis H, Langlois L, Gouty S, Dacher M, Sheopard R, Cox BM & Nugent FS. Morphine-induced synaptic abnormalities in the VTA are reversed by HDAC inhibition. J. Neurophysiol. 116(3): 1093-1103, 2016.
Fereshteh S. Nugent, Ph.D.
Name: Fereshteh S. Nugent, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
USU faculty
Faculty Rank:
Associate Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Synaptic plasticity, Reward Pathway, Addiction Neuorpsychiatric Disorders
Novel Anidepressants
Email:
Office Phone:
(301) 295-3243
Department Website:
Education
Ph.D., Neurophysiology, Tarbiat Modarres University, Tehran, Iran, 2003
Postdoctoral, Neuroscience, Brown University
Postdoctoral, Neuroscience, Brown University
Biography
Synaptic Plasticity of the Reward Pathway
Since the discovery of synaptic plasticity as the cellular correlate of learning and memory, strong overlaps between neural and cellular substrates of learning, drug addiction and stress-related disorders have been recognized. Yet it remains a major challenge to identify the neural circuits and synaptic mechanisms contributing to abnormalities in dopamine signaling induced by addictive drugs and adverse early life experiences. The major focus of my laboratory is the elucidation of synaptic mechanisms underlying reward learning, drug addiction and neuropsychiatric disorders such as depression, with particular emphasis on the midbrain dopamine system originating from the ventral tegmental area (VTA) and its control by the lateral habenula (LHb). Research in our laboratory also explores effects of severe early life stress on synaptic transmission and plasticity of distinct VTA dopamine circuits to identify the neural circuits and molecular mechanisms contributing to abnormalities in dopamine signaling induced by adverse early life experiences. To achieve these goals, we use a combination of immunohistochemical, biochemical, epigenetic, electrophysiological and behavioral techniques. We expect that identifying novel epigenetic mechanisms in the regulation of synaptic plasticity and memory formation in midbrain dopamine circuits will point to new directions in pharmacotherapy for drug addiction and stress-related disorders.
Selected Publications
Authement M.E., L. L. D., Shepard R.D., Browne C.A., Lucki L., Kassis H., Nugent F.S., A role for corticotrophin releasing factor signaling in the lateral habenula and its modulation by early life stress, Science Signaling, 11(520) (2018), Featured as the cover story
Summary: http://stke.sciencemag.org/cgi/content/summary/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Abstract: http://stke.sciencemag.org/cgi/content/abstract/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Reprint: http://stke.sciencemag.org/cgi/reprint/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Full text: http://stke.sciencemag.org/cgi/content/full/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Langlois, L.D. and Nugent F.S. Opiates and plasticity in ventral tegmental area, Invited Review, ACS Chemical Neuroscience, 20;8(9):1830-1838 (2017)
Authement M.E., Kodangattil J.N.,Gouty,S., Rusnak, M., Symes A.J., Cox B.M., and Nugent F.S., Histone deacetylase inhibition rescues maternal deprivation-induced GABAergic metaplasticity through restoration of AKAP signaling, Neuron, 86: 1240–1252 (2015)
Kodangattil J.N., Dacher M.A., Authement, M.E. and Nugent F.S., Spike timing-dependent plasticity at GABAergic synapses in the Ventral tegmental area. Journal of Physiology, 591.19: 4699-710 (2013)
Dacher, M. A., Gouty, S., Dash, S., Cox, B.M., and Nugent, F.S., A-kinase anchoring protein-calcineurin signaling in long-term depression of GABAergic synapses, Journal of Neuroscience, 33:2650-60 (2013)
Nugent, F.S., Penick, E.C., Kauer, J.A., Opiates block long-term potentiation of GABAergic synapses. Nature, 466: 1086-1095 (2007)
Postdoctoral Fellows: Dr. Ludovic Langlois
Graduate Students: Ryan Shepard
Lab Alumni: Dr. Matthieu Dacher (Université Pierre et Marie Curie, France), Dr. Jayaraj N. Kodangattil, Dr. Haifa Kassis, Dr. Michael Authement (NIAAA) and Steven Dash
Since the discovery of synaptic plasticity as the cellular correlate of learning and memory, strong overlaps between neural and cellular substrates of learning, drug addiction and stress-related disorders have been recognized. Yet it remains a major challenge to identify the neural circuits and synaptic mechanisms contributing to abnormalities in dopamine signaling induced by addictive drugs and adverse early life experiences. The major focus of my laboratory is the elucidation of synaptic mechanisms underlying reward learning, drug addiction and neuropsychiatric disorders such as depression, with particular emphasis on the midbrain dopamine system originating from the ventral tegmental area (VTA) and its control by the lateral habenula (LHb). Research in our laboratory also explores effects of severe early life stress on synaptic transmission and plasticity of distinct VTA dopamine circuits to identify the neural circuits and molecular mechanisms contributing to abnormalities in dopamine signaling induced by adverse early life experiences. To achieve these goals, we use a combination of immunohistochemical, biochemical, epigenetic, electrophysiological and behavioral techniques. We expect that identifying novel epigenetic mechanisms in the regulation of synaptic plasticity and memory formation in midbrain dopamine circuits will point to new directions in pharmacotherapy for drug addiction and stress-related disorders.
Selected Publications
Authement M.E., L. L. D., Shepard R.D., Browne C.A., Lucki L., Kassis H., Nugent F.S., A role for corticotrophin releasing factor signaling in the lateral habenula and its modulation by early life stress, Science Signaling, 11(520) (2018), Featured as the cover story
Summary: http://stke.sciencemag.org/cgi/content/summary/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Abstract: http://stke.sciencemag.org/cgi/content/abstract/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Reprint: http://stke.sciencemag.org/cgi/reprint/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Full text: http://stke.sciencemag.org/cgi/content/full/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Langlois, L.D. and Nugent F.S. Opiates and plasticity in ventral tegmental area, Invited Review, ACS Chemical Neuroscience, 20;8(9):1830-1838 (2017)
Authement M.E., Kodangattil J.N.,Gouty,S., Rusnak, M., Symes A.J., Cox B.M., and Nugent F.S., Histone deacetylase inhibition rescues maternal deprivation-induced GABAergic metaplasticity through restoration of AKAP signaling, Neuron, 86: 1240–1252 (2015)
Kodangattil J.N., Dacher M.A., Authement, M.E. and Nugent F.S., Spike timing-dependent plasticity at GABAergic synapses in the Ventral tegmental area. Journal of Physiology, 591.19: 4699-710 (2013)
Dacher, M. A., Gouty, S., Dash, S., Cox, B.M., and Nugent, F.S., A-kinase anchoring protein-calcineurin signaling in long-term depression of GABAergic synapses, Journal of Neuroscience, 33:2650-60 (2013)
Nugent, F.S., Penick, E.C., Kauer, J.A., Opiates block long-term potentiation of GABAergic synapses. Nature, 466: 1086-1095 (2007)
Postdoctoral Fellows: Dr. Ludovic Langlois
Graduate Students: Ryan Shepard
Lab Alumni: Dr. Matthieu Dacher (Université Pierre et Marie Curie, France), Dr. Jayaraj N. Kodangattil, Dr. Haifa Kassis, Dr. Michael Authement (NIAAA) and Steven Dash
Ying-Hong Feng, M.D., Ph.D
Name: Ying-Hong Feng, M.D., Ph.D
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Dr.
Faculty Rank:
Associate Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Receptor structure-function & signaling; Epigenome editing & transcription regulation
Translational research in neurodegenerative diseases, mood disorder, cancer, diabetes, and cardiovascular diseases
Email:
Office Phone:
(301) 295-3232
Department Website:
Education
1978-1983, M.D., Wuhan University School of Medicine, Wuhan, China
1990-1994, Ph.D., Biochemistry, University of Oxford, Oxford, UK
1994-1997, Postdoctoral, Molecular Cardiology, Cleveland Clinic Foundation
1990-1994, Ph.D., Biochemistry, University of Oxford, Oxford, UK
1994-1997, Postdoctoral, Molecular Cardiology, Cleveland Clinic Foundation
Biography
Feng’s lab has three research programs. The first is about crosstalk signaling of receptors in the form of receptor dimerization in pathophysiology such as vascular inflammation, metabolism (type 2 diabetes), pain (silent myocardial ischemia), depression, immunosuppression, cancer progression, and etc. The second is about translational research on neurodegenerative diseases and cancer with focus on novel splicing variants, of critical genes that are known to play an important role in depression, neurodegeneration, neuroregeneration, exosome biology, tumorigenesis, and cancer progression. The last is to develop novel technologies for genome editing and epigenome editing.
Representative publications, projects, and/or deployments
- Feng YH, Li X, Zeng R, Gorodeski GI. Endogenously Expressed Truncated P2X7 Receptor Lacking the C-Terminus is Preferentially Upregulated in Epithelial Cancer Cells and Fails to Mediate Ligand-Induced Pore Formation and Apoptosis. Nucleosides Nucleotides Nucleic Acids. 25:1271-6 (2006)
- Feng YH, Li X, Zeng R, Gorodeski GI. Endogenously expressed truncated P2X7 receptor lacking the C-terminus is preferentially upregulated in epithelial cancer cells and fails to mediate ligand-induced pore formation and apoptosis. Nucleosides Nucleotides Nucleic Acids. 25(9-11):1271-6 (2006)
- Chen M, Wang T, Liao ZX, Pan XL, Feng YH, Wang H. Nicotine-induced prenatal overexposure to maternal glucocorticoid and intrauterine growth retardation in rat. Exp Toxicol Pathol. 59: 245-51 (2007)
- 30. Zhang X, Wang G, Dupre DJ, Feng Y, Robitaille M, Lazartigues E, Feng YH, Hebert TE, Wu G. Rab1 GTPase and dimerization in the cell surface expression of angiotensin II type 2 receptor. J Pharmacol Exp Ther. 330(1):109-17 (2009)
- 31. Guo J, Li ZC and Feng YH. Expression and activation of the reprogramming transcription factors. Biochem Biophys Res Commun. 390(4):1081-6 (2009)
- 32. Zhang J, Villacorta L, Chang L, Fan Z, Hamblin M, Zhu T, Chen CS, Cole MP, Schopfer FJ, Deng CX, Garcia-Barrio MT, Feng YH, Freeman BA, Chen YE. Nitrated oleic acid inhibits Angiotensin II-induced hypertension. Circ Res, 107(4):540-8 (2010)
- 34. Day RD, Lee YH, Han L, Kim YC, Feng YH. Angiotensin II activates AMPK for execution of apoptosis through energy-dependent and -independent mechanisms. Am J Physiol Lung Cell Mol Physiol, 301(5):L772-81 (2011)
- 35. Wang TT, Chen M, Liu L, Cheng H, Yan YE, Feng YH*, Wang H. Nicotine induces a single CpG methylation in the StAR promoter: a potential mechanism for reduced StAR expression and cortisol production. Toxicol and Applied Pharmacol. 257(3):328-37 (2011) *Co-senior author
- 37. Wang H, Yin H, Yan F, Sun M, Du L, Peng W, Li Q, Feng Y, Zhou Y. Folate-mediated mitochondrial targeting with doxorubicin-polyrotaxane nanoparticles overcomes multidrug resistance. Oncotarget. 6(5):2827-42 (2015).
- 38. Li K, Pang J, Cheng H, Wei-Peng Liu WP, Chen MK, Yun Luo Y, Di JM, Zhang H, Huang WT, Li LY, Shao CK, Feng YH*, Gao X. Manipulation of prostate cancer metastasis by locus-specific modification of the CRMP4 promoter region using chimeric TALE DNA methyltransferase and demethylase. Oncotarget. 6(12):10030-44 (2015) *Co-senior author
Bibliography
- Feng YH, Saad Y and Karnik SS. Reversible Inactivation of AT2 Angiotensin II Receptor from Cysteine-Disulfide Bond Exchange. FEBS Letters 484, 133-138 (2000)
- Feng YH, Sun Y, and Douglas JG. G??-Independent Constitutive Association of Gs? with SHP-1 and Angiotensin II Receptor AT2 Is Essential in AT2-mediated Activation of SHP-1. Proc. Natl. Acad. Sci. USA 99:12049-12054 (2002)
- Wang Q, Li X, Wang L, Feng YH, Zeng R, Gorodeski GI. Anti-apoptotic effects of estrogen in normal and in cancer human cervical epithelial cells. Endocrinology 145:5568-79 (2004)
- Wang Q, Wang L, Feng YH, Li X, Zeng R, Gorodeski GI. P2X7-receptor-mediated apoptosis of human cervical epithelial cells. Am J Physiol Cell Physiol. 287:C1349-58 (2004)
- Wang L, Feng YH, Gorodeski GI. EGF facilitates epinephrine inhibition of P2X7-receptor pore formation by modulating 2-adrenoceptor internalization and recycling: a signaling network. Endocrinology 146:164-74 (2005)
- Feng YH, Zhou LY, Sun Y, and Douglas JG. Functional Diversity of AT2 Receptor Orthologues in Closely related Eutherian. Kidney Intl 67:1731-8 (2005)
- eng YH, Wang L, Wang Q, Li X, Zeng R, Gorodeski GI. ATP ligation stimulates GRK-3 - mediated phosphorylation and -arrestin-2- and dynamin-dependent internalization of the P2X7-receptor. Am J Physiol Cell Physiol. 288:C1342-56 (2005)
- Feng YH, Zhou L, Qiu R, and Robin Zeng. Single mutations at Asn295 and Leu305 in the cytoplasmic half of TM7 of the AT1 receptor induce promiscuous agonist specificity for angiotensin II fragments - A PSEUDO-CONSTITUTIVE ACTIVITY. Mol Pharmacol 68:347-55 (2005)
- Feng YH, Ding Y, Ren S, Xu C, Karnik SS. Unconventional homologous internalization of the AT1 receptor induced by G protein-independent signals. Hypertension 46:419-25 (2005)
- Feng YH, Li X, Wang L, Zhou L, Gorodeski GI. A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization. J Biol Chem. 281:17228-37 (2006)
Irwin Lucki, Ph.D.
Name: Irwin Lucki, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Professor and Chair
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Neuropharmacology
Antidepressant drugs
Email:
Office Phone:
(301) 295-3248
Education
Education: 1972 B.A. University of Illinois, Psychology
1976 M.A. University of Iowa, Psychology
1979 Ph.D. University of Iowa, Biopsychology
Postgraduate Training:
1979-1981 Postdoctoral Research Fellow, Psychopharmacology Training Program, Department of Psychiatry, University of Pennsylvania
1976 M.A. University of Iowa, Psychology
1979 Ph.D. University of Iowa, Biopsychology
Postgraduate Training:
1979-1981 Postdoctoral Research Fellow, Psychopharmacology Training Program, Department of Psychiatry, University of Pennsylvania
Biography
Selected from 180 publications:
Cryan, J.F., Valentino, R.J. and Lucki, I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neuroscience and Biobehavioral Reviews, 2005, 29:547-569.
Valentino, R.J., Lucki, I. and Van Bockstaele, E. Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction. Brain Research, 2010, 1314:29-37. PMC2819581
Ho, N., Sommers, M.S. and Lucki, I. Effects of diabetes on hippocampal neurogenesis: Links to cognition and depression. Neuroscience and Biobehavioral Reviews, 2013, 37:1346-1362. PMC3788092
Browne, C.A. and Lucki, I. Mechanisms mediating the antidepressant-like Lucki, I. The spectrum of behaviors influenced by serotonin. Biological Psychiatry, 1998, 44:151-162.
Page, M.E., Cryan, J.F., Sullivan, A., Dalvi, A. and Lucki, I. Behavioral and neurochemical effects of EMD 68843: A combined selective inhibitor of serotonin reuptake and partial 5-HT1A receptor agonist. Journal of Pharmacology and Experimental Therapeutics, 2002, 302:1-8.
Carr, G.V. and Lucki, I. The role of serotonin receptor subtypes in treating depression: A review of animal studies. Psychopharmacology, 2011, 213:265-287. PMC3374933
Carr, G.V., Schechter, L.E. and Lucki, I. Antidepressant and anxiolytic effects of
selective 5-HT6 receptor agonists in rats. Psychopharmacology, 2011, 213:499-507. PMC2910165
effects of ketamine: Screening for fast-acting novel antidepressants. Frontiers in Neuropharmacology, 2013, 4:161, 1-18. PMC3873522.
Mayorga, A.J., Dalvi, A., Page, M.E., Zimov-Levinson, S., Hen R. and Lucki, I. Antidepressant-like behavioral effects in 5-HT1A and 5-HT1B receptor mutant mice. Journal of Pharmacology and Experimental Therapeutics, 2001, 298:1101-1107.
Cryan, J.F., O’Leary, O.F., Jin, S.-H., Friedland, J.C., Ouyang, M., Hirsch, B.R., Page, M.E., Dalvi, A., Thomas, S.A. and Lucki, I. Norepinephrine deficient mice lack responses to antidepressant drugs, including SSRIs. Proceedings of the National Academy of Sciences, 2004, 101:8186-8191.
O’Leary, O.F., Bechtholt, A.J., Crowley, J.J., Valentino, R.J. and Lucki, I. The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs. European Neuropsychopharmacology, 2007, 17:215-226.
Balu, D.T., Turner, J.R., Brookshire, B.R., Hill, T.E., Blendy, J.A. and Lucki, I. Brain monoamines and responses to antidepressant drugs in MRL/MpJ versus C57BL/6J and mice. Neuropharmacology, 2013, 67:503-510. PMC437180
Cryan, J.F., Markou, A. and Lucki, I. Assessing antidepressant-like activity in laboratory animals: Recent developments and future needs. Trends in Pharmacological Sciences, 2002, 23(5): 238-245.
Crowley, J.J. and Lucki, I. Opportunities to discover genes regulating depression and antidepressant response from rodent behavioral genetics. Current Pharmaceutical Design, 11:157-169, 2005.
Bechtholt, A.J., Valentino, R.J. and Lucki, I. Overlapping and distinct brain regions associated
with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine. Neuropsychopharmacology, 2008, 33:2117-2130.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Price, M. L., Curtis, A.L., Kirby, L.G., Valentino, R.J. and Lucki, I. Biphasic effects of corticotropin-releasing factor on brain serotonergic activity. Neuropsychopharmacology, 1998, 18:492-502.
Price, M.L. and Lucki, I. Regulation of serotonin release in the lateral septum and striatum by corticotropin-releasing factor. Journal of Neuroscience, 2001, 21:2833-2841.
Howard, O., Carr, G.V., Hill, T.E., Valentino, R.J. and Lucki, I. Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin. Psychopharmacology, 2008, 199:569-82. PMC2744742
Snyder, K.P., Hill-Smith, T.E., Lucki, I. and Valentino, R.J. Corticotropin-releasing factor in the rat dorsal raphe nucleus promotes different forms of behavioral flexibility depending on social stress history. Neuropsychopharmacology, 2015, 40:2517-25. PMCID in process.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Falcon, E., Maier, K., Robinson, S.A. and Lucki, I. Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice. Psychopharmacology, 2015, 232:907-915. PMC4326609
Browne, C.A., van Nest, D. and Lucki, I. Antidepressant-like effects of buprenorphine in rats are strain dependent. Behavioural Brain Research, 2015, 278:385-392. PMC4382376
Falcon, E., Browne, C.A., Leon, R.M., Fleites, V.C., Sweeney, R., Kirby, L.G. and Lucki, I. Antidepressant-like effects of buprenorphine are mediated by kappa opioid receptors. Neuropsychopharmacology, 2016, 41(9):2344-2351. PMC4946065
A full bibliography of over 170 peer-reviewed publications is available at: http://www.ncbi.nlm.nih.gov/sites/myncbi/irwin.lucki.1/bibliography/45296221/public/?sort=date&direction=ascending.
Cryan, J.F., Valentino, R.J. and Lucki, I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neuroscience and Biobehavioral Reviews, 2005, 29:547-569.
Valentino, R.J., Lucki, I. and Van Bockstaele, E. Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction. Brain Research, 2010, 1314:29-37. PMC2819581
Ho, N., Sommers, M.S. and Lucki, I. Effects of diabetes on hippocampal neurogenesis: Links to cognition and depression. Neuroscience and Biobehavioral Reviews, 2013, 37:1346-1362. PMC3788092
Browne, C.A. and Lucki, I. Mechanisms mediating the antidepressant-like Lucki, I. The spectrum of behaviors influenced by serotonin. Biological Psychiatry, 1998, 44:151-162.
Page, M.E., Cryan, J.F., Sullivan, A., Dalvi, A. and Lucki, I. Behavioral and neurochemical effects of EMD 68843: A combined selective inhibitor of serotonin reuptake and partial 5-HT1A receptor agonist. Journal of Pharmacology and Experimental Therapeutics, 2002, 302:1-8.
Carr, G.V. and Lucki, I. The role of serotonin receptor subtypes in treating depression: A review of animal studies. Psychopharmacology, 2011, 213:265-287. PMC3374933
Carr, G.V., Schechter, L.E. and Lucki, I. Antidepressant and anxiolytic effects of
selective 5-HT6 receptor agonists in rats. Psychopharmacology, 2011, 213:499-507. PMC2910165
effects of ketamine: Screening for fast-acting novel antidepressants. Frontiers in Neuropharmacology, 2013, 4:161, 1-18. PMC3873522.
Mayorga, A.J., Dalvi, A., Page, M.E., Zimov-Levinson, S., Hen R. and Lucki, I. Antidepressant-like behavioral effects in 5-HT1A and 5-HT1B receptor mutant mice. Journal of Pharmacology and Experimental Therapeutics, 2001, 298:1101-1107.
Cryan, J.F., O’Leary, O.F., Jin, S.-H., Friedland, J.C., Ouyang, M., Hirsch, B.R., Page, M.E., Dalvi, A., Thomas, S.A. and Lucki, I. Norepinephrine deficient mice lack responses to antidepressant drugs, including SSRIs. Proceedings of the National Academy of Sciences, 2004, 101:8186-8191.
O’Leary, O.F., Bechtholt, A.J., Crowley, J.J., Valentino, R.J. and Lucki, I. The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs. European Neuropsychopharmacology, 2007, 17:215-226.
Balu, D.T., Turner, J.R., Brookshire, B.R., Hill, T.E., Blendy, J.A. and Lucki, I. Brain monoamines and responses to antidepressant drugs in MRL/MpJ versus C57BL/6J and mice. Neuropharmacology, 2013, 67:503-510. PMC437180
Cryan, J.F., Markou, A. and Lucki, I. Assessing antidepressant-like activity in laboratory animals: Recent developments and future needs. Trends in Pharmacological Sciences, 2002, 23(5): 238-245.
Crowley, J.J. and Lucki, I. Opportunities to discover genes regulating depression and antidepressant response from rodent behavioral genetics. Current Pharmaceutical Design, 11:157-169, 2005.
Bechtholt, A.J., Valentino, R.J. and Lucki, I. Overlapping and distinct brain regions associated
with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine. Neuropsychopharmacology, 2008, 33:2117-2130.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Price, M. L., Curtis, A.L., Kirby, L.G., Valentino, R.J. and Lucki, I. Biphasic effects of corticotropin-releasing factor on brain serotonergic activity. Neuropsychopharmacology, 1998, 18:492-502.
Price, M.L. and Lucki, I. Regulation of serotonin release in the lateral septum and striatum by corticotropin-releasing factor. Journal of Neuroscience, 2001, 21:2833-2841.
Howard, O., Carr, G.V., Hill, T.E., Valentino, R.J. and Lucki, I. Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin. Psychopharmacology, 2008, 199:569-82. PMC2744742
Snyder, K.P., Hill-Smith, T.E., Lucki, I. and Valentino, R.J. Corticotropin-releasing factor in the rat dorsal raphe nucleus promotes different forms of behavioral flexibility depending on social stress history. Neuropsychopharmacology, 2015, 40:2517-25. PMCID in process.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Falcon, E., Maier, K., Robinson, S.A. and Lucki, I. Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice. Psychopharmacology, 2015, 232:907-915. PMC4326609
Browne, C.A., van Nest, D. and Lucki, I. Antidepressant-like effects of buprenorphine in rats are strain dependent. Behavioural Brain Research, 2015, 278:385-392. PMC4382376
Falcon, E., Browne, C.A., Leon, R.M., Fleites, V.C., Sweeney, R., Kirby, L.G. and Lucki, I. Antidepressant-like effects of buprenorphine are mediated by kappa opioid receptors. Neuropsychopharmacology, 2016, 41(9):2344-2351. PMC4946065
A full bibliography of over 170 peer-reviewed publications is available at: http://www.ncbi.nlm.nih.gov/sites/myncbi/irwin.lucki.1/bibliography/45296221/public/?sort=date&direction=ascending.
Representative publications, projects, and/or deployments
- 2007 - present, Principal Field Editor, Psychopharmacology
- 1995 - present, Editorial Advisory Board, Neuropsychopharmacology
- 2014 – present, Editorial Advisory Board, Neurobiology of Stress
- Buprenorphine for Depression and Anxiety.PI. NIMH, R01 MH92412, 2012-2018. Total direct costs = $1,250,000. The goal of this grant is to examine animal models supporting the development of buprenorphine for the clinical treatment of depression and anxiety.
- Kappa Receptor Antagonists as Rapid Acting Antidepressants. PI. NIMH, R01 MH105623, 2016-2020. Total direct costs = $1,000,000. The goal of this grant is to study animal models supporting the development of novel kappa receptor antagonists for the clinical treatment of mood disorders.
- Training Program in Neuropsychopharmacology. NIMH, T32 MH14654-34-38, 1978-2021. I was Training Program Director at the University of Pennsylvania 1992-2016.
- Regulation of Hippocampal Neurogenesis by Antidepressants. PI. NIMH, R01 MH86599, 2009-2015.
- Biology of Serotonin in Brain; Program Project Grant: Irwin Lucki, Ph.D., Program Director (1994-2007). NIMH, PO1-MH-48125.
- Regulation of Neurogenesis by Stress and Antidepressants. Program Director. National Cooperative Drug Discovery Group involving University of Pennsylvania and Wyeth Neuroscience. U01-MH 72832, 2005-2009.
Bibliography
- 2016- present Professor (with tenure) and Chair, Department of Pharmacology and Molecular Therapeutics, Uniformed University of the Health Sciences, Bethesda MD
- 2016-present Professor, Department of Psychiatry, Uniformed University of the Health Sciences, Bethesda MD
- 1996-2016 Professor of Psychology in Psychiatry (with tenure), Depts. of Psychiatry and Pharmacology, University of Pennsylvania, Philadelphia PA
- 1990-1996 Associate Professor of Psychology in Psychiatry (with tenure), Depts. of Psychiatry and Pharmacology, University of Pennsylvania, Philadelphia PA
- 1989-1990 Assistant Professor, Department of Pharmacology, University of Pennsylvania, Philadelphia PA
- 1984-1990 Assistant Professor of Psychology in Psychiatry, Department of Psychiatry, University of Pennsylvania, Philadelphia PA
- 1981-1984 Research Associate, Department of Psychiatry, University of Pennsylvania, Philadelphia PA
Aviva J Symes, Ph.D.
Name: Aviva J Symes, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Traumatic brain injury
Role of renin angiotensin system in the brain after injury
Email:
Office Phone:
(301) 295-3234
Education
B.Sc.(Hons). Biochemistry, University of Manchester, UK
Ph.D. Biochemistry/Molecular Biology, University College London, UK
Post-doctoral training: Massachusetts General Hospital/ Harvard Medical School, Boston.
Ph.D. Biochemistry/Molecular Biology, University College London, UK
Post-doctoral training: Massachusetts General Hospital/ Harvard Medical School, Boston.
Biography
RESEARCH INTERESTS:
My lab aims to understand the mechanisms through which the brain responds to traumatic injury and more specifically to delineate the pathways through which detrimental neuroinflammatory cascades can be altered to enhance recovery after injury. The initial lesion can produce significant tissue damage and breakdown of the blood brain barrier. These immediate effects lead to activation of many secondary cascades involving interplay between endogenous surviving neurons and glia, and infiltrating cells and molecules from the bloodstream. Injury therefore leads to acute neuroinflammatory cascades, and also to more chronic inflammatory effects. Indeed, activated microglia have been documented in postmortem brains many years after the initial insult. Our lab focuses on understanding the molecular signaling cascades that occur after injury in addition to testing potential therapeutics to enhance recovery from injury. We currently utilize several different rodent models of traumatic brain injury (TBI), with assays ranging from behavioral through molecular to understand the complex interactions that occur after injury, and to determine how manipulations may impact on functional recovery. We also utilize primary cell cultures to tease apart the molecular signaling pathways that contribute to inflammation after injury.
Angiotensin receptor blockers as potential therapeutics for TBI
Angiotensin receptor blockers (ARBs) are widely used FDA-approved anti-hypertension drugs with a favorable side effect profile that have been used as a mechanism for reducing the amount of TGF-β signaling in several different organ systems. In the CNS, ARBs have also been shown to be neuroprotective, anti-inflammatory and protective of the cerebral blood flow (CBF). The brain possesses its own renin angiotensin system, with many different components of the system expressed in the different cell types in the brain. However, in addition to acting as antagonists at the Angiotensin II receptor 1 (AT1R) some ARBs also possess potent PPARγ agonist activity that enhances their anti-inflammatory action. We have demonstrated that the ARB candesartan, lessens inflammation, reduces lesion volume, limits glial reactivity, increases neuronal survival and improves motor and cognitive recovery up to 28 days after injury. These beneficial effects are seen when low-dose candesartan is administered up to 6 hours after injury, a clinically acceptable therapeutic window. Our data suggest that both AT1 receptor antagonism and PPARγ agonism contribute to the efficacy of ARB treatment after TBI and it is this multimodal action by a single drug that makes it a strong candidate for TBI clinical trials. We are pursuing translational studies for candesartan for brain injury in addition to investigating the consequences of TBI on the endogenous renin-angiotensin system in the brain.
TGF-β signaling after injury
TGF-β is an injury induced cytokine that has complex roles in the central nervous system. After brain injury TGF-β can promote astrogliosis and enhance the deposition of molecules inhibitory to regeneration in the glial scar. Yet TGF-β is also neuroprotective indicating the sometimes conflicting roles of this cytokine. We have shown that after a penetrating brain injury mice that lack expression of the TGF-β signaling molecule Smad3, form a glial scar more quickly, with a smaller scar, than wild type mice. However, we also found that Smad3 null mice have more pronounced neuronal loss after injury. Thus, global interference with TGF-β signaling is not a desirable therapeutic option. Further, TGF-β is anti-inflammatory in some contexts – so chronic repression of TGF-β signaling pathways may enhance inflammation. In primary microglial cultures we have shown that inflammatory pathways downregulate TGF-β receptor expression, allowing for prolonged enhancement of the inflammatory activated state.
My lab aims to understand the mechanisms through which the brain responds to traumatic injury and more specifically to delineate the pathways through which detrimental neuroinflammatory cascades can be altered to enhance recovery after injury. The initial lesion can produce significant tissue damage and breakdown of the blood brain barrier. These immediate effects lead to activation of many secondary cascades involving interplay between endogenous surviving neurons and glia, and infiltrating cells and molecules from the bloodstream. Injury therefore leads to acute neuroinflammatory cascades, and also to more chronic inflammatory effects. Indeed, activated microglia have been documented in postmortem brains many years after the initial insult. Our lab focuses on understanding the molecular signaling cascades that occur after injury in addition to testing potential therapeutics to enhance recovery from injury. We currently utilize several different rodent models of traumatic brain injury (TBI), with assays ranging from behavioral through molecular to understand the complex interactions that occur after injury, and to determine how manipulations may impact on functional recovery. We also utilize primary cell cultures to tease apart the molecular signaling pathways that contribute to inflammation after injury.
Angiotensin receptor blockers as potential therapeutics for TBI
Angiotensin receptor blockers (ARBs) are widely used FDA-approved anti-hypertension drugs with a favorable side effect profile that have been used as a mechanism for reducing the amount of TGF-β signaling in several different organ systems. In the CNS, ARBs have also been shown to be neuroprotective, anti-inflammatory and protective of the cerebral blood flow (CBF). The brain possesses its own renin angiotensin system, with many different components of the system expressed in the different cell types in the brain. However, in addition to acting as antagonists at the Angiotensin II receptor 1 (AT1R) some ARBs also possess potent PPARγ agonist activity that enhances their anti-inflammatory action. We have demonstrated that the ARB candesartan, lessens inflammation, reduces lesion volume, limits glial reactivity, increases neuronal survival and improves motor and cognitive recovery up to 28 days after injury. These beneficial effects are seen when low-dose candesartan is administered up to 6 hours after injury, a clinically acceptable therapeutic window. Our data suggest that both AT1 receptor antagonism and PPARγ agonism contribute to the efficacy of ARB treatment after TBI and it is this multimodal action by a single drug that makes it a strong candidate for TBI clinical trials. We are pursuing translational studies for candesartan for brain injury in addition to investigating the consequences of TBI on the endogenous renin-angiotensin system in the brain.
TGF-β signaling after injury
TGF-β is an injury induced cytokine that has complex roles in the central nervous system. After brain injury TGF-β can promote astrogliosis and enhance the deposition of molecules inhibitory to regeneration in the glial scar. Yet TGF-β is also neuroprotective indicating the sometimes conflicting roles of this cytokine. We have shown that after a penetrating brain injury mice that lack expression of the TGF-β signaling molecule Smad3, form a glial scar more quickly, with a smaller scar, than wild type mice. However, we also found that Smad3 null mice have more pronounced neuronal loss after injury. Thus, global interference with TGF-β signaling is not a desirable therapeutic option. Further, TGF-β is anti-inflammatory in some contexts – so chronic repression of TGF-β signaling pathways may enhance inflammation. In primary microglial cultures we have shown that inflammatory pathways downregulate TGF-β receptor expression, allowing for prolonged enhancement of the inflammatory activated state.
Bibliography
Biosketch Link:
- Bone morphogenetic protein-2-mediated pain and inflammation in a rat model of posterolateral arthrodesis. Mitchell K, Shah JP, Dalgard CL, Tsytsikova LV, Tipton AC, Dmitriev AE, Symes AJ. BMC neuroscience. 2016; 17(1):80. PubMed [journal]PMID: 27905881 PMCID: PMC5134101
- Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Villapol S, Balarezo MG, Affram K, Saavedra JM, Symes AJ. Brain : a journal of neurology. 2015; 138(Pt 11):3299-315. PubMed [journal]PMID: 26115674 PMCID: PMC4731413
- Runx1 promotes proliferation and neuronal differentiation in adult mouse neurosphere cultures. Logan TT, Rusnak M, Symes AJ. Stem cell research. 2015; 15(3):554-564. PubMed [journal]PMID: 26473321
- Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan. Villapol S, Kryndushkin D, Balarezo MG, Campbell AM, Saavedra JM, Shewmaker FP, Symes AJ. The American journal of pathology. 2015; 185(10):2641-52. PubMed [journal]PMID: 26435412 PMCID: PMC4607758
- . Temporal patterns of cortical proliferation of glial cell populations after traumatic brain injury in mice. Susarla BT, Villapol S, Yi JH, Geller HM, Symes AJ. ASN neuro. 2014; 6(3):159-70. PubMed [journal]PMID: 24670035 PMCID: PMC4013687
- LPS antagonism of TGF-β signaling results in prolonged survival and activation of rat primary microglia. Mitchell K, Shah JP, Tsytsikova LV, Campbell AM, Affram K, Symes AJ. Journal of neurochemistry. 2014; 129(1):155-68. PubMed [journal]PMID: 24251648
- Temporal dynamics of cerebral blood flow, cortical damage, apoptosis, astrocyte-vasculature interaction and astrogliosis in the pericontusional region after traumatic brain injury. Villapol S, Byrnes KR, Symes AJ. Frontiers in neurology. 2014; 5:82. PubMed [journal]PMID: 24926283 PMCID: PMC4044679
- Smad3 deficiency increases cortical and hippocampal neuronal loss following traumatic brain injury. Villapol S, Wang Y, Adams M, Symes AJ. Experimental neurology. 2013; 250:353-65. PubMed [journal]PMID: 24120438
- TGF-β superfamily gene expression and induction of the Runx1 transcription factor in adult neurogenic regions after brain injury. Logan TT, Villapol S, Symes AJ. PloS one. 2013; 8(3):e59250. PubMed [journal]PMID: 23555640 PMCID: PMC3605457
- Candesartan, an angiotensin II AT₁-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice. Villapol S, Yaszemski AK, Logan TT, Sánchez-Lemus E, Saavedra JM, Symes AJ. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2012; 37(13):2817-29. PubMed [journal]PMID: 22892395 PMCID: PMC3499714
PHA - Cellular & Molecular Pharmacology
Regina M Day, Ph.D.
Name: Regina M Day, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Vice Chair
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Email:
Office Phone:
(301) 295-3236
Education
A.B. Smith College, Northampton, MA, USA
Ph.D. Tufts University, Boston, MA, USA
Ph.D. Tufts University, Boston, MA, USA
Ying-Hong Feng, M.D., Ph.D
Name: Ying-Hong Feng, M.D., Ph.D
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Dr.
Faculty Rank:
Associate Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Receptor structure-function & signaling; Epigenome editing & transcription regulation
Translational research in neurodegenerative diseases, mood disorder, cancer, diabetes, and cardiovascular diseases
Email:
Office Phone:
(301) 295-3232
Department Website:
Education
1978-1983, M.D., Wuhan University School of Medicine, Wuhan, China
1990-1994, Ph.D., Biochemistry, University of Oxford, Oxford, UK
1994-1997, Postdoctoral, Molecular Cardiology, Cleveland Clinic Foundation
1990-1994, Ph.D., Biochemistry, University of Oxford, Oxford, UK
1994-1997, Postdoctoral, Molecular Cardiology, Cleveland Clinic Foundation
Biography
Feng’s lab has three research programs. The first is about crosstalk signaling of receptors in the form of receptor dimerization in pathophysiology such as vascular inflammation, metabolism (type 2 diabetes), pain (silent myocardial ischemia), depression, immunosuppression, cancer progression, and etc. The second is about translational research on neurodegenerative diseases and cancer with focus on novel splicing variants, of critical genes that are known to play an important role in depression, neurodegeneration, neuroregeneration, exosome biology, tumorigenesis, and cancer progression. The last is to develop novel technologies for genome editing and epigenome editing.
Representative publications, projects, and/or deployments
- Feng YH, Li X, Zeng R, Gorodeski GI. Endogenously Expressed Truncated P2X7 Receptor Lacking the C-Terminus is Preferentially Upregulated in Epithelial Cancer Cells and Fails to Mediate Ligand-Induced Pore Formation and Apoptosis. Nucleosides Nucleotides Nucleic Acids. 25:1271-6 (2006)
- Feng YH, Li X, Zeng R, Gorodeski GI. Endogenously expressed truncated P2X7 receptor lacking the C-terminus is preferentially upregulated in epithelial cancer cells and fails to mediate ligand-induced pore formation and apoptosis. Nucleosides Nucleotides Nucleic Acids. 25(9-11):1271-6 (2006)
- Chen M, Wang T, Liao ZX, Pan XL, Feng YH, Wang H. Nicotine-induced prenatal overexposure to maternal glucocorticoid and intrauterine growth retardation in rat. Exp Toxicol Pathol. 59: 245-51 (2007)
- 30. Zhang X, Wang G, Dupre DJ, Feng Y, Robitaille M, Lazartigues E, Feng YH, Hebert TE, Wu G. Rab1 GTPase and dimerization in the cell surface expression of angiotensin II type 2 receptor. J Pharmacol Exp Ther. 330(1):109-17 (2009)
- 31. Guo J, Li ZC and Feng YH. Expression and activation of the reprogramming transcription factors. Biochem Biophys Res Commun. 390(4):1081-6 (2009)
- 32. Zhang J, Villacorta L, Chang L, Fan Z, Hamblin M, Zhu T, Chen CS, Cole MP, Schopfer FJ, Deng CX, Garcia-Barrio MT, Feng YH, Freeman BA, Chen YE. Nitrated oleic acid inhibits Angiotensin II-induced hypertension. Circ Res, 107(4):540-8 (2010)
- 34. Day RD, Lee YH, Han L, Kim YC, Feng YH. Angiotensin II activates AMPK for execution of apoptosis through energy-dependent and -independent mechanisms. Am J Physiol Lung Cell Mol Physiol, 301(5):L772-81 (2011)
- 35. Wang TT, Chen M, Liu L, Cheng H, Yan YE, Feng YH*, Wang H. Nicotine induces a single CpG methylation in the StAR promoter: a potential mechanism for reduced StAR expression and cortisol production. Toxicol and Applied Pharmacol. 257(3):328-37 (2011) *Co-senior author
- 37. Wang H, Yin H, Yan F, Sun M, Du L, Peng W, Li Q, Feng Y, Zhou Y. Folate-mediated mitochondrial targeting with doxorubicin-polyrotaxane nanoparticles overcomes multidrug resistance. Oncotarget. 6(5):2827-42 (2015).
- 38. Li K, Pang J, Cheng H, Wei-Peng Liu WP, Chen MK, Yun Luo Y, Di JM, Zhang H, Huang WT, Li LY, Shao CK, Feng YH*, Gao X. Manipulation of prostate cancer metastasis by locus-specific modification of the CRMP4 promoter region using chimeric TALE DNA methyltransferase and demethylase. Oncotarget. 6(12):10030-44 (2015) *Co-senior author
Bibliography
- Feng YH, Saad Y and Karnik SS. Reversible Inactivation of AT2 Angiotensin II Receptor from Cysteine-Disulfide Bond Exchange. FEBS Letters 484, 133-138 (2000)
- Feng YH, Sun Y, and Douglas JG. G??-Independent Constitutive Association of Gs? with SHP-1 and Angiotensin II Receptor AT2 Is Essential in AT2-mediated Activation of SHP-1. Proc. Natl. Acad. Sci. USA 99:12049-12054 (2002)
- Wang Q, Li X, Wang L, Feng YH, Zeng R, Gorodeski GI. Anti-apoptotic effects of estrogen in normal and in cancer human cervical epithelial cells. Endocrinology 145:5568-79 (2004)
- Wang Q, Wang L, Feng YH, Li X, Zeng R, Gorodeski GI. P2X7-receptor-mediated apoptosis of human cervical epithelial cells. Am J Physiol Cell Physiol. 287:C1349-58 (2004)
- Wang L, Feng YH, Gorodeski GI. EGF facilitates epinephrine inhibition of P2X7-receptor pore formation by modulating 2-adrenoceptor internalization and recycling: a signaling network. Endocrinology 146:164-74 (2005)
- Feng YH, Zhou LY, Sun Y, and Douglas JG. Functional Diversity of AT2 Receptor Orthologues in Closely related Eutherian. Kidney Intl 67:1731-8 (2005)
- eng YH, Wang L, Wang Q, Li X, Zeng R, Gorodeski GI. ATP ligation stimulates GRK-3 - mediated phosphorylation and -arrestin-2- and dynamin-dependent internalization of the P2X7-receptor. Am J Physiol Cell Physiol. 288:C1342-56 (2005)
- Feng YH, Zhou L, Qiu R, and Robin Zeng. Single mutations at Asn295 and Leu305 in the cytoplasmic half of TM7 of the AT1 receptor induce promiscuous agonist specificity for angiotensin II fragments - A PSEUDO-CONSTITUTIVE ACTIVITY. Mol Pharmacol 68:347-55 (2005)
- Feng YH, Ding Y, Ren S, Xu C, Karnik SS. Unconventional homologous internalization of the AT1 receptor induced by G protein-independent signals. Hypertension 46:419-25 (2005)
- Feng YH, Li X, Wang L, Zhou L, Gorodeski GI. A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization. J Biol Chem. 281:17228-37 (2006)
Sergey Iordanskiy, Ph.D.
Name: Sergey Iordanskiy, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Assistant Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Molecular biology of retroviruses and host genomes; Effect of cellular stress on virus latency and replication; Exosomes in intercellular communication and cytopathogenesis.
Lentiviral vectors for delivery and expression of genome editing tools; Coinfection of HIV and human blood parasites.
Email:
Office Phone:
(301) 295-0580
Department Website:
Education
B.S & M.S., Biochemistry, Moscow State University of Education, Moscow, Russia
Ph.D., Cellular Biology, Moscow State University of Education & Ivanovsky Research Institute of Virology, Russian Academy of Medical Sciences
Postdoctoral Training, Molecular Biology of AIDS, Picower Institute for Medical Research, Manhasset, NY
Postdoctoral Training, Molecular Virology, George Washington University, Washington, DC
Ph.D., Cellular Biology, Moscow State University of Education & Ivanovsky Research Institute of Virology, Russian Academy of Medical Sciences
Postdoctoral Training, Molecular Biology of AIDS, Picower Institute for Medical Research, Manhasset, NY
Postdoctoral Training, Molecular Virology, George Washington University, Washington, DC
Biography
RESEARCH INTERESTS
Radiation-induced cellular stress and human endogenous retroviruses
Human endogenous retroviruses (HERVs) constitute from 5 to 9% of human genome. Most of integrated HERV genomes are silenced. However, detection of high levels of HERV-K mRNA, proteins, and even virions in a wide range of cancers suggests that some HERVs may play an essential role in cancer development. HERV-K subgroup HML-2 is involved into the activation of various types of cancer. Recent studies revealed dramatic increase of HERV-K and -R transcription in the prostate, breast and colon cancer after standard doses of radiotherapy. Our studies of the effect of radiation doses used for cancer therapy on the cells latently-infected with another retrovirus, HIV-1, in the context of HIV-related cancer, revealed inappropriate entry and arrest at S phase of the cell cycle, induction of viral transcription and enhanced apoptotic response predominantly in the infected cells. We examine pathogenic effect of integrated retroviruses in the cells, exposed to different irradiation doses, including X-ray and gamma doses used for cancer therapy and neutrons. We focus on the mechanism of activation of retroviral promoters, gene expression, translation and secretion of HERV proteins using chromatin immunoprecipitation, transcriptomic and proteomic analysis. Important part of our study is analysis of the impact of extracellular viral RNA, proteins and likely released HERV virions on unexposed cells. Another aspect of our study is testing of key HERV RNA and proteins for their potential to be used as biomarkers of different radiation doses. Our ultimate goal is to determine retrovirus-mediated side effects of radiotherapeutic treatment and environmental radiation and to find prospective targets and interventions to counteract this influence.
Exosomes in cytopathogenesis and intercellular communications within context of radiation-induced stress.
Initially small extracellular vesicles, exosomes, were thought to be a mechanism for discarding unwanted cellular material. However, in recent years, numerous evidence has indicated the role of exosomes in intercellular communication and the progression of various pathologies, including cancer and multiple neurodegenerative disorders. Exosomes are cell-derived vesicles that are present in all biological fluids and are capable of carrying RNAs and proteins which can be exchanged from cell-to-cell. Existing data indicate that exosomes and their cargo play crucial roles in communicating of radiation-induced and bystander cells with the result related to DNA damage and cell pathogenesis. We recently demonstrated multiple pathogenic effects of exosomes from the cells containing integrated retroviral genomes, such as human T lymphotropic virus 1 (HTLV-1) and HIV-1 on naïve cells. These effects were enhanced by the exposure of producing cells to ionizing radiation. Current research in our laboratory is focused on the analysis of host-cellular and viral cargo in the exosomes released from the radiation-exposed cells. We also investigate how non radiation-exposed cells respond to exosome-mediated effect of radiation in the context of radiotherapy and environmental radiation. Potential outcomes include understanding of the functions of exosome-packaged micro- and mRNAs, viral and host proteins in recipient cells and their pathogenic impact that is related to radiation. Identification of exosome-incorporated biomarkers of radiation doses is also part of this study.
Collaborative Projects
Our laboratory is involved in collaborative projects with George Washington University (Paul Brindley Lab) and Massachusetts Institute of Technology (Kevin Esvelt Lab). These studies are related to coinfection of HIV and human blood fluke Schistosoma mansoni and S. hematobium and the use of HIV-based lentiviral vectors for delivery of gene editing tools within the context of Gene Drive strategy.
Radiation-induced cellular stress and human endogenous retroviruses
Human endogenous retroviruses (HERVs) constitute from 5 to 9% of human genome. Most of integrated HERV genomes are silenced. However, detection of high levels of HERV-K mRNA, proteins, and even virions in a wide range of cancers suggests that some HERVs may play an essential role in cancer development. HERV-K subgroup HML-2 is involved into the activation of various types of cancer. Recent studies revealed dramatic increase of HERV-K and -R transcription in the prostate, breast and colon cancer after standard doses of radiotherapy. Our studies of the effect of radiation doses used for cancer therapy on the cells latently-infected with another retrovirus, HIV-1, in the context of HIV-related cancer, revealed inappropriate entry and arrest at S phase of the cell cycle, induction of viral transcription and enhanced apoptotic response predominantly in the infected cells. We examine pathogenic effect of integrated retroviruses in the cells, exposed to different irradiation doses, including X-ray and gamma doses used for cancer therapy and neutrons. We focus on the mechanism of activation of retroviral promoters, gene expression, translation and secretion of HERV proteins using chromatin immunoprecipitation, transcriptomic and proteomic analysis. Important part of our study is analysis of the impact of extracellular viral RNA, proteins and likely released HERV virions on unexposed cells. Another aspect of our study is testing of key HERV RNA and proteins for their potential to be used as biomarkers of different radiation doses. Our ultimate goal is to determine retrovirus-mediated side effects of radiotherapeutic treatment and environmental radiation and to find prospective targets and interventions to counteract this influence.
Exosomes in cytopathogenesis and intercellular communications within context of radiation-induced stress.
Initially small extracellular vesicles, exosomes, were thought to be a mechanism for discarding unwanted cellular material. However, in recent years, numerous evidence has indicated the role of exosomes in intercellular communication and the progression of various pathologies, including cancer and multiple neurodegenerative disorders. Exosomes are cell-derived vesicles that are present in all biological fluids and are capable of carrying RNAs and proteins which can be exchanged from cell-to-cell. Existing data indicate that exosomes and their cargo play crucial roles in communicating of radiation-induced and bystander cells with the result related to DNA damage and cell pathogenesis. We recently demonstrated multiple pathogenic effects of exosomes from the cells containing integrated retroviral genomes, such as human T lymphotropic virus 1 (HTLV-1) and HIV-1 on naïve cells. These effects were enhanced by the exposure of producing cells to ionizing radiation. Current research in our laboratory is focused on the analysis of host-cellular and viral cargo in the exosomes released from the radiation-exposed cells. We also investigate how non radiation-exposed cells respond to exosome-mediated effect of radiation in the context of radiotherapy and environmental radiation. Potential outcomes include understanding of the functions of exosome-packaged micro- and mRNAs, viral and host proteins in recipient cells and their pathogenic impact that is related to radiation. Identification of exosome-incorporated biomarkers of radiation doses is also part of this study.
Collaborative Projects
Our laboratory is involved in collaborative projects with George Washington University (Paul Brindley Lab) and Massachusetts Institute of Technology (Kevin Esvelt Lab). These studies are related to coinfection of HIV and human blood fluke Schistosoma mansoni and S. hematobium and the use of HIV-based lentiviral vectors for delivery of gene editing tools within the context of Gene Drive strategy.
Bibliography
Biosketch Link:
- Suttiprapa S, Rinaldi G, Tsai IJ, Mann VH, Dubrovsky L, Yan HB, Holroyd N, Huckvale T, Durrant C, Protasio AV, Pushkarsky T, Iordanskiy S, Berriman M, Bukrinsky MI and PJ Brindley, HIV-1 Integrates Widely throughout the Genome of the Human Blood Fluke Schistosoma mansoni. PLoS Pathog. 2016 Oct 20;12(10):e1005931.
- Santos S, Obukhov Y, Nekhai S, Pushkarsky T, Brichacek B, Bukrinsky M and S Iordanskiy. Cellular minichromosome maintenance complex component 5 (MCM5) is incorporated into HIV-1 virions and modulates viral replication in the newly infected cells, Virology. 2016 Oct;497:11-22.
- Iordanskiy S and F Kashanchi, Potential of radiation-induced cellular stress for reactivation of latent HIV-1 and killing of infected cells. AIDS Res Hum Retroviruses. 2016 32(2):120-124.
- Sampey G, Saifuddin M, Schwab A, Barclay R, Punya S, Chung M-Y, Hakami RM, Asad Zadeh M, Lepene B, Klase ZA, El-Hage N, Young M, Iordanskiy S and F Kashanchi, Exosomes from HIV-1 infected cells stimulate production of pro-inflammatory cytokines through TAR RNA. J Biol Chem. 2016 291(3):1251-1266.
- Iordanskiy S, Van Duyne R, Sampey GC, Woodson CM, Fry K, Saifuddin M, Guo J, Wu Y, Romerio F and F Kashanchi, Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells. Virology 2015, 485:1–15.
- Guendel I, Iordanskiy S, Van Duyne R, Kehn-Hall K, Saifuddin M, Das R, Jaworski E, Sampey G, Senina S, Shultz L, Narayanan A, Chen H, Lepene B, Zeng C, and F. Kashanchi, Novel neuroprotective GSK-3β inhibitor restricts Tat-mediated HIV-1 replication. J Virol 2014, 88(2): 1189-1208
- Narayanan A, Iordanskiy S, Das R, Van Duyne R, Santos S, Jaworski E, Guendel I, Sampey G, Gerhart E, Iglesias-Ussel M, Popratiloff A, Hakami R, Kehn-Hall K, Young M, Subra C, Gilbert C, Bailey C, Romerio F and F. Kashanchi, Exosomes derived from HIV-1 infected cells contain TAR RNA. J Biol Chem. 2013 288(27): 20014-20033.
- Santos S, Obukhov Y, Nekhai S, Bukrinsky M and S Iordanskiy, Virus-producing cells determine the host protein profiles of HIV-1 virion cores. Retrovirology. 2012, 9:65.
- Iordanskiy S, Berro R, Altieri M, Kashanchi F. and M. Bukrinsky, Intracytoplasmic maturation of the human immunodeficiency virus type 1 reverse transcription complexes determines their capacity to integrate into chromatin. Retrovirology 2006. 3: 4
- Iordanskiy S, Zhao Y, DiMarzio P, Agostini I, Dubrovsky L, and M. Bukrinsky, Heat-shock protein 70 exerts opposing effects on Vpr-dependent and Vpr-independent HIV-1 replication in macrophages. Blood. 2004. 104: 1867-1872.
Robert L Kortum, M.D., Ph.D.
Name: Robert L Kortum, M.D., Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Assistant Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Cancer Cell Signaling
Ras
Email:
Office Phone:
(301) 295-3249
Department Website:
Education
Ph.D. - University of Nebraska Medical School, 2004
M.D. - University of Nebraska Medical School, 2006
M.D. - University of Nebraska Medical School, 2006
Bibliography
Biosketch Link:
Frank Shewmaker, Ph.D.
Name: Frank Shewmaker, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Assistant Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Email:
Office Phone:
(301) 295-3527
Andrew L Snow, Ph.D.
Name: Andrew L Snow, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Associate Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
human immunology, lymphocyte signaling & apoptosis, primary immune disorders
Email:
Office Phone:
(301) 295-3267
Education
B.S., Biology, Visual Arts, Duke University
Ph.D., Immunology, Stanford University School of Medicine
Postdoctoral Training, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH
Ph.D., Immunology, Stanford University School of Medicine
Postdoctoral Training, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH
Biography
RESEARCH INTERESTS
The major emphasis of my laboratory is to elucidate how aberrations in lymphocyte signaling contribute to deranged immune homeostasis in novel lymphoproliferative disorders and primary immunodeficiencies. Our research focuses on identifying novel molecular regulators of lymphocyte apoptosis and differentiation in humans, with the ultimate goal of informing new therapeutic approaches for controlling immune responses by manipulating cell death sensitivity.
ONGOING PROJECTS
1. Signal regulation and physiological relevance of specific T cell apoptosis pathways
The regulation and eventual contraction of activated T cells during an immune response is critical for maintaining equilibrium in the immune system and preventing unwanted damage to host tissues. Normally, specific apoptosis programs induced by T cell receptor (TCR) restimulation or cytokine withdrawal work to cull the majority of activated effector T cells, leaving a small pool of memory T cells behind to protect against subsequent infections (Fig 1). We now appreciate that genetic defects in lymphocyte apoptosis directly contribute to excess lymphoproliferation in humans. For example, T cells from patients with X-linked lymphoproliferative disease (XLP-1) display a profound defect in T cell receptor restimulation-induced cell death (RICD; also known as activation-induced cell death), a critical self-regulatory apoptosis program that constrains effector T cell expansion. Our lab has defined several biochemical mechanisms by which signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which is lost or mutated in XLP patients, facilitates RICD. Most recently, we led an international collaborative effort demonstrating that inhibition of diacylglycerol kinase alpha (DGKa), a modulatory enzyme with elevated activity in SAP-deficient T cells, presents a viable therapeutic approach for treating EBV-induced fulminant mononucleosis in XLP-1 patients, via restoration of RICD. Collectively, this work underscores the physiological relevance of RICD in preventing excessive T cell accumulation, severe immunopathology and mortality in XLP patients infected with EBV. We continue to investigate how RICD sensitivity is “tuned” via SAP-dependent signals.
We are also investigating novel links between metabolic programming and apoptosis sensitivity in human T cells. Our recent work indicates that while excessive anabolic metabolism (i.e. glycolysis) leaves effector T cells more susceptible to RICD, catabolic metabolism (i.e. autophagy) can protect T cells derived from distinct memory compartments from death induced by cytokine withdrawal. We have delineated specific molecular mechanisms responsible for these changes in cell death sensitivity, and continue to investigate how specific metabolic programs affect T cell viability. Our work illuminates how metabolic changes govern T cell survival, and may explain why certain memory T cells give rise to a larger, more robust effector response (via reduced cell death) that better protects the host when challenged with a pathogen or tumor.
2. Novel immunological disorders linked to mutations in CARD11
We discovered that gain-of-function (GOF) mutations in the CARD11 gene cause a rare congenital B cell lymphoproliferative disorder called B cell Expansion with NF-kB and T cell Anergy (BENTA) disease. My laboratory has taken a leading role in the genetic diagnosis and phenotypic characterization of an expanding cohort of BENTA patients (Fig 2). CARD11 encodes a scaffolding protein that links antigen receptor signaling to NF-kB activation in lymphocytes. Unlike the wild-type protein, CARD11 GOF mutants spontaneously oligomerize and drive constitutive activation of NF-kB, contributing to increased proliferation and enhanced survival of both immature and naïve patient B cells. Surprisingly, BENTA patients also exhibit hallmarks of immunodeficiency, including B cell differentiation defects, selective antibody deficiency, and opportunistic viral infections (e.g. molluscum contagiousum, chronic EBV) that reflect impaired T cell responses. Our latest findings pinpoint intrinsic molecular defects in plasma cell differentiation and antibody secretion in activated BENTA patient B cells, despite profound apoptosis resistance that likely explains excessive B cell expansion.
In collaboration with Dr. Joshua Milner (NIH) and others, we are also investigating loss-of-function (LOF) CARD11 mutations in atopic patients with severe eczema. We recently described 4 families with distinct, hypomorphic CARD11 mutations that dominantly interfere with WT CARD11 signaling, resulting in impaired NF-kB and mTORC1 signaling. Extensive structure-function studies of the CARD11 molecule continue in my lab, drawing from an expanding list of natural mutations in human patients. Using cell transfection systems, murine models and primary patient lymphocytes, my lab also continues to investigate how both GOF and LOF CARD11 mutations perturb signaling, differentiation and function of B and T cells.
The major emphasis of my laboratory is to elucidate how aberrations in lymphocyte signaling contribute to deranged immune homeostasis in novel lymphoproliferative disorders and primary immunodeficiencies. Our research focuses on identifying novel molecular regulators of lymphocyte apoptosis and differentiation in humans, with the ultimate goal of informing new therapeutic approaches for controlling immune responses by manipulating cell death sensitivity.
ONGOING PROJECTS
1. Signal regulation and physiological relevance of specific T cell apoptosis pathways
The regulation and eventual contraction of activated T cells during an immune response is critical for maintaining equilibrium in the immune system and preventing unwanted damage to host tissues. Normally, specific apoptosis programs induced by T cell receptor (TCR) restimulation or cytokine withdrawal work to cull the majority of activated effector T cells, leaving a small pool of memory T cells behind to protect against subsequent infections (Fig 1). We now appreciate that genetic defects in lymphocyte apoptosis directly contribute to excess lymphoproliferation in humans. For example, T cells from patients with X-linked lymphoproliferative disease (XLP-1) display a profound defect in T cell receptor restimulation-induced cell death (RICD; also known as activation-induced cell death), a critical self-regulatory apoptosis program that constrains effector T cell expansion. Our lab has defined several biochemical mechanisms by which signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which is lost or mutated in XLP patients, facilitates RICD. Most recently, we led an international collaborative effort demonstrating that inhibition of diacylglycerol kinase alpha (DGKa), a modulatory enzyme with elevated activity in SAP-deficient T cells, presents a viable therapeutic approach for treating EBV-induced fulminant mononucleosis in XLP-1 patients, via restoration of RICD. Collectively, this work underscores the physiological relevance of RICD in preventing excessive T cell accumulation, severe immunopathology and mortality in XLP patients infected with EBV. We continue to investigate how RICD sensitivity is “tuned” via SAP-dependent signals.
We are also investigating novel links between metabolic programming and apoptosis sensitivity in human T cells. Our recent work indicates that while excessive anabolic metabolism (i.e. glycolysis) leaves effector T cells more susceptible to RICD, catabolic metabolism (i.e. autophagy) can protect T cells derived from distinct memory compartments from death induced by cytokine withdrawal. We have delineated specific molecular mechanisms responsible for these changes in cell death sensitivity, and continue to investigate how specific metabolic programs affect T cell viability. Our work illuminates how metabolic changes govern T cell survival, and may explain why certain memory T cells give rise to a larger, more robust effector response (via reduced cell death) that better protects the host when challenged with a pathogen or tumor.
2. Novel immunological disorders linked to mutations in CARD11
We discovered that gain-of-function (GOF) mutations in the CARD11 gene cause a rare congenital B cell lymphoproliferative disorder called B cell Expansion with NF-kB and T cell Anergy (BENTA) disease. My laboratory has taken a leading role in the genetic diagnosis and phenotypic characterization of an expanding cohort of BENTA patients (Fig 2). CARD11 encodes a scaffolding protein that links antigen receptor signaling to NF-kB activation in lymphocytes. Unlike the wild-type protein, CARD11 GOF mutants spontaneously oligomerize and drive constitutive activation of NF-kB, contributing to increased proliferation and enhanced survival of both immature and naïve patient B cells. Surprisingly, BENTA patients also exhibit hallmarks of immunodeficiency, including B cell differentiation defects, selective antibody deficiency, and opportunistic viral infections (e.g. molluscum contagiousum, chronic EBV) that reflect impaired T cell responses. Our latest findings pinpoint intrinsic molecular defects in plasma cell differentiation and antibody secretion in activated BENTA patient B cells, despite profound apoptosis resistance that likely explains excessive B cell expansion.
In collaboration with Dr. Joshua Milner (NIH) and others, we are also investigating loss-of-function (LOF) CARD11 mutations in atopic patients with severe eczema. We recently described 4 families with distinct, hypomorphic CARD11 mutations that dominantly interfere with WT CARD11 signaling, resulting in impaired NF-kB and mTORC1 signaling. Extensive structure-function studies of the CARD11 molecule continue in my lab, drawing from an expanding list of natural mutations in human patients. Using cell transfection systems, murine models and primary patient lymphocytes, my lab also continues to investigate how both GOF and LOF CARD11 mutations perturb signaling, differentiation and function of B and T cells.
Bibliography
Biosketch Link:
- Voss K, Larsen SE, Snow AL. 2017. Metabolic reprogramming and apoptosis sensitivity: defining the contours of a T cell response. Cancer Letters 408:190-96.
- Arjunaraja S, Nosé BD, Sukumar G, Lott NM, Dalgard CL, Snow AL. 2017. Intrinsic Plasma Cell Differentiation Defects in BENTA Patient B Cells. Frontiers in Immunology 8: 913.
- Larsen SE, Voss K, Laing ED, Snow AL. 2017. Differential cytokine withdrawal-induced death sensitivity of effector T cells derived from distinct human CD8+ memory subsets. Cell Death Discovery 3:17031.
- Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ, Reynolds PR, Lyons JJ, Nelson CG, Ruffo E, Dorjbal B, Glauzy S, Stoddard J, Niemela J, Rosenzweig SD, McElwee JJ, DiMaggio T, Stone KD, Palma A, Oleastro M, Prieto E, Bernasconi A, Dubra G, Danielian S, Zaiat J, Marti M, Kim B, Cooper MA, Romberg N, Meffre E, Gelfand EW*, Snow AL*, Milner JD*. 2017. “Germline hypomorphic CARD11 mutations in severe atopic disease.” Nature Genetics 49:1192-1201.
- Larsen SE, Bilenkin A, Snow AL. 2017. Sensitivity to restimulation-induced cell death is linked to glycolytic metabolism in human T cells. Journal of Immunology 198: 147-55.
- Ruffo E, Malacarne V, Larsen SE, Das R, Patrussi L, Wulfing C, Biskup C, Schwartzberg PL, Baldari TC, Rubio I, Nichols KE*, Snow AL*, Baldanzi G*, Graziani A*. 2016. Inhibition of diacylglycerol kinase alpha restores TCR-induced diacylglycerol signaling and restimulation-induced cell death in XLP-1 T lymphocytes. Science Translational Medicine 8: 321ra7.
- Brohl AS, Stinson JR, Su HC, Badgett T, Jennings CD, Sukumar G, Sindiri S, Wang W, Moir S, Dalgard CL, Moscow JA, Khan J, Snow AL. 2015. Germline CARD11 mutation in a patient with severe congenital B cell lymphocytosis. Journal of Clinical Immunology, 35: 32-46. ePub Oct 2014.
- Katz G, Krummey SM, Larsen SE, Stinson JR, Snow AL. 2014. SAP facilitates recruitment and activation of LCK at NTB-A receptors during restimulation-induced cell death. Journal of Immunology 192: 4202-9.
- Snow AL, Xiao W, Chaigne-Delalande B, Pittaluga S, Stinson JR, Matthews HF, Lu W, Zheng L, Schmitz R, Jhavar S, Kuchen S, Lamborn IT, Jing H, Raffeld M, Su HC, Staudt LM, Lenardo MJ. 2012. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. Journal of Experimental Medicine 209: 2247-61.
- Snow AL, Marsh RA, Krummey SM, Roehrs P, Young LR, Zhang K, van Hoff J, Dhar D, Nichols KE, Filipovich AH, Su HC, Bleesing JJ, Lenardo MJ. 2009. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. Journal of Clinical Investigation 119: 2976-2989.
PHA - Radioprotectants
Regina M Day, Ph.D.
Name: Regina M Day, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Vice Chair
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Email:
Office Phone:
(301) 295-3236
Education
A.B. Smith College, Northampton, MA, USA
Ph.D. Tufts University, Boston, MA, USA
Ph.D. Tufts University, Boston, MA, USA
Sergey Iordanskiy, Ph.D.
Name: Sergey Iordanskiy, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Assistant Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Molecular biology of retroviruses and host genomes; Effect of cellular stress on virus latency and replication; Exosomes in intercellular communication and cytopathogenesis.
Lentiviral vectors for delivery and expression of genome editing tools; Coinfection of HIV and human blood parasites.
Email:
Office Phone:
(301) 295-0580
Department Website:
Education
B.S & M.S., Biochemistry, Moscow State University of Education, Moscow, Russia
Ph.D., Cellular Biology, Moscow State University of Education & Ivanovsky Research Institute of Virology, Russian Academy of Medical Sciences
Postdoctoral Training, Molecular Biology of AIDS, Picower Institute for Medical Research, Manhasset, NY
Postdoctoral Training, Molecular Virology, George Washington University, Washington, DC
Ph.D., Cellular Biology, Moscow State University of Education & Ivanovsky Research Institute of Virology, Russian Academy of Medical Sciences
Postdoctoral Training, Molecular Biology of AIDS, Picower Institute for Medical Research, Manhasset, NY
Postdoctoral Training, Molecular Virology, George Washington University, Washington, DC
Biography
RESEARCH INTERESTS
Radiation-induced cellular stress and human endogenous retroviruses
Human endogenous retroviruses (HERVs) constitute from 5 to 9% of human genome. Most of integrated HERV genomes are silenced. However, detection of high levels of HERV-K mRNA, proteins, and even virions in a wide range of cancers suggests that some HERVs may play an essential role in cancer development. HERV-K subgroup HML-2 is involved into the activation of various types of cancer. Recent studies revealed dramatic increase of HERV-K and -R transcription in the prostate, breast and colon cancer after standard doses of radiotherapy. Our studies of the effect of radiation doses used for cancer therapy on the cells latently-infected with another retrovirus, HIV-1, in the context of HIV-related cancer, revealed inappropriate entry and arrest at S phase of the cell cycle, induction of viral transcription and enhanced apoptotic response predominantly in the infected cells. We examine pathogenic effect of integrated retroviruses in the cells, exposed to different irradiation doses, including X-ray and gamma doses used for cancer therapy and neutrons. We focus on the mechanism of activation of retroviral promoters, gene expression, translation and secretion of HERV proteins using chromatin immunoprecipitation, transcriptomic and proteomic analysis. Important part of our study is analysis of the impact of extracellular viral RNA, proteins and likely released HERV virions on unexposed cells. Another aspect of our study is testing of key HERV RNA and proteins for their potential to be used as biomarkers of different radiation doses. Our ultimate goal is to determine retrovirus-mediated side effects of radiotherapeutic treatment and environmental radiation and to find prospective targets and interventions to counteract this influence.
Exosomes in cytopathogenesis and intercellular communications within context of radiation-induced stress.
Initially small extracellular vesicles, exosomes, were thought to be a mechanism for discarding unwanted cellular material. However, in recent years, numerous evidence has indicated the role of exosomes in intercellular communication and the progression of various pathologies, including cancer and multiple neurodegenerative disorders. Exosomes are cell-derived vesicles that are present in all biological fluids and are capable of carrying RNAs and proteins which can be exchanged from cell-to-cell. Existing data indicate that exosomes and their cargo play crucial roles in communicating of radiation-induced and bystander cells with the result related to DNA damage and cell pathogenesis. We recently demonstrated multiple pathogenic effects of exosomes from the cells containing integrated retroviral genomes, such as human T lymphotropic virus 1 (HTLV-1) and HIV-1 on naïve cells. These effects were enhanced by the exposure of producing cells to ionizing radiation. Current research in our laboratory is focused on the analysis of host-cellular and viral cargo in the exosomes released from the radiation-exposed cells. We also investigate how non radiation-exposed cells respond to exosome-mediated effect of radiation in the context of radiotherapy and environmental radiation. Potential outcomes include understanding of the functions of exosome-packaged micro- and mRNAs, viral and host proteins in recipient cells and their pathogenic impact that is related to radiation. Identification of exosome-incorporated biomarkers of radiation doses is also part of this study.
Collaborative Projects
Our laboratory is involved in collaborative projects with George Washington University (Paul Brindley Lab) and Massachusetts Institute of Technology (Kevin Esvelt Lab). These studies are related to coinfection of HIV and human blood fluke Schistosoma mansoni and S. hematobium and the use of HIV-based lentiviral vectors for delivery of gene editing tools within the context of Gene Drive strategy.
Radiation-induced cellular stress and human endogenous retroviruses
Human endogenous retroviruses (HERVs) constitute from 5 to 9% of human genome. Most of integrated HERV genomes are silenced. However, detection of high levels of HERV-K mRNA, proteins, and even virions in a wide range of cancers suggests that some HERVs may play an essential role in cancer development. HERV-K subgroup HML-2 is involved into the activation of various types of cancer. Recent studies revealed dramatic increase of HERV-K and -R transcription in the prostate, breast and colon cancer after standard doses of radiotherapy. Our studies of the effect of radiation doses used for cancer therapy on the cells latently-infected with another retrovirus, HIV-1, in the context of HIV-related cancer, revealed inappropriate entry and arrest at S phase of the cell cycle, induction of viral transcription and enhanced apoptotic response predominantly in the infected cells. We examine pathogenic effect of integrated retroviruses in the cells, exposed to different irradiation doses, including X-ray and gamma doses used for cancer therapy and neutrons. We focus on the mechanism of activation of retroviral promoters, gene expression, translation and secretion of HERV proteins using chromatin immunoprecipitation, transcriptomic and proteomic analysis. Important part of our study is analysis of the impact of extracellular viral RNA, proteins and likely released HERV virions on unexposed cells. Another aspect of our study is testing of key HERV RNA and proteins for their potential to be used as biomarkers of different radiation doses. Our ultimate goal is to determine retrovirus-mediated side effects of radiotherapeutic treatment and environmental radiation and to find prospective targets and interventions to counteract this influence.
Exosomes in cytopathogenesis and intercellular communications within context of radiation-induced stress.
Initially small extracellular vesicles, exosomes, were thought to be a mechanism for discarding unwanted cellular material. However, in recent years, numerous evidence has indicated the role of exosomes in intercellular communication and the progression of various pathologies, including cancer and multiple neurodegenerative disorders. Exosomes are cell-derived vesicles that are present in all biological fluids and are capable of carrying RNAs and proteins which can be exchanged from cell-to-cell. Existing data indicate that exosomes and their cargo play crucial roles in communicating of radiation-induced and bystander cells with the result related to DNA damage and cell pathogenesis. We recently demonstrated multiple pathogenic effects of exosomes from the cells containing integrated retroviral genomes, such as human T lymphotropic virus 1 (HTLV-1) and HIV-1 on naïve cells. These effects were enhanced by the exposure of producing cells to ionizing radiation. Current research in our laboratory is focused on the analysis of host-cellular and viral cargo in the exosomes released from the radiation-exposed cells. We also investigate how non radiation-exposed cells respond to exosome-mediated effect of radiation in the context of radiotherapy and environmental radiation. Potential outcomes include understanding of the functions of exosome-packaged micro- and mRNAs, viral and host proteins in recipient cells and their pathogenic impact that is related to radiation. Identification of exosome-incorporated biomarkers of radiation doses is also part of this study.
Collaborative Projects
Our laboratory is involved in collaborative projects with George Washington University (Paul Brindley Lab) and Massachusetts Institute of Technology (Kevin Esvelt Lab). These studies are related to coinfection of HIV and human blood fluke Schistosoma mansoni and S. hematobium and the use of HIV-based lentiviral vectors for delivery of gene editing tools within the context of Gene Drive strategy.
Bibliography
Biosketch Link:
- Suttiprapa S, Rinaldi G, Tsai IJ, Mann VH, Dubrovsky L, Yan HB, Holroyd N, Huckvale T, Durrant C, Protasio AV, Pushkarsky T, Iordanskiy S, Berriman M, Bukrinsky MI and PJ Brindley, HIV-1 Integrates Widely throughout the Genome of the Human Blood Fluke Schistosoma mansoni. PLoS Pathog. 2016 Oct 20;12(10):e1005931.
- Santos S, Obukhov Y, Nekhai S, Pushkarsky T, Brichacek B, Bukrinsky M and S Iordanskiy. Cellular minichromosome maintenance complex component 5 (MCM5) is incorporated into HIV-1 virions and modulates viral replication in the newly infected cells, Virology. 2016 Oct;497:11-22.
- Iordanskiy S and F Kashanchi, Potential of radiation-induced cellular stress for reactivation of latent HIV-1 and killing of infected cells. AIDS Res Hum Retroviruses. 2016 32(2):120-124.
- Sampey G, Saifuddin M, Schwab A, Barclay R, Punya S, Chung M-Y, Hakami RM, Asad Zadeh M, Lepene B, Klase ZA, El-Hage N, Young M, Iordanskiy S and F Kashanchi, Exosomes from HIV-1 infected cells stimulate production of pro-inflammatory cytokines through TAR RNA. J Biol Chem. 2016 291(3):1251-1266.
- Iordanskiy S, Van Duyne R, Sampey GC, Woodson CM, Fry K, Saifuddin M, Guo J, Wu Y, Romerio F and F Kashanchi, Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells. Virology 2015, 485:1–15.
- Guendel I, Iordanskiy S, Van Duyne R, Kehn-Hall K, Saifuddin M, Das R, Jaworski E, Sampey G, Senina S, Shultz L, Narayanan A, Chen H, Lepene B, Zeng C, and F. Kashanchi, Novel neuroprotective GSK-3β inhibitor restricts Tat-mediated HIV-1 replication. J Virol 2014, 88(2): 1189-1208
- Narayanan A, Iordanskiy S, Das R, Van Duyne R, Santos S, Jaworski E, Guendel I, Sampey G, Gerhart E, Iglesias-Ussel M, Popratiloff A, Hakami R, Kehn-Hall K, Young M, Subra C, Gilbert C, Bailey C, Romerio F and F. Kashanchi, Exosomes derived from HIV-1 infected cells contain TAR RNA. J Biol Chem. 2013 288(27): 20014-20033.
- Santos S, Obukhov Y, Nekhai S, Bukrinsky M and S Iordanskiy, Virus-producing cells determine the host protein profiles of HIV-1 virion cores. Retrovirology. 2012, 9:65.
- Iordanskiy S, Berro R, Altieri M, Kashanchi F. and M. Bukrinsky, Intracytoplasmic maturation of the human immunodeficiency virus type 1 reverse transcription complexes determines their capacity to integrate into chromatin. Retrovirology 2006. 3: 4
- Iordanskiy S, Zhao Y, DiMarzio P, Agostini I, Dubrovsky L, and M. Bukrinsky, Heat-shock protein 70 exerts opposing effects on Vpr-dependent and Vpr-independent HIV-1 replication in macrophages. Blood. 2004. 104: 1867-1872.
Vijay K. Singh, Ph.D.
Name: Vijay K. Singh, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Prof.
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Radiation Biology
Countermeasures
Email:
Office Phone:
(301) 295-2347
Department Website:
Education
1983 Ph.D., Central Drug Research Institute (KU), India
1978 M.Sc., Kanpur University, India
1975 B.Sc., Magadh University, India
1978 M.Sc., Kanpur University, India
1975 B.Sc., Magadh University, India
Biography
Mechanism of radiation injury and advanced development of radiation countermeasures
My laboratory focuses attention on the molecular basis of radiation injury which results in acute radiation syndromes (ARS), and the mechanism of action of potential radiation countermeasures. Our ultimate goal is to develop radiation countermeasures to protect military personnel, first responders and civilians from succumbing to ARS following radiation exposure whether it is accidental or as a result of deliberate attack. To achieve this goal we are currently investigating the mechanism of action of gamma-tocotrienol (GT3, an isomer of Vitamin E), Ex-RAD (a chlorobenzylsulphone derivative), toll-like receptor (TLR) ligands (CBLB502), and anti-ceramide antibody at the cellular level, by evaluating cell signaling pathways (cytokine expression, p53 pathway, TLR activation) including DNA damage and repair pathways.
In collaboration with corporate partners, my lab is developing several radiation countermeasures which are under advanced stages of development. CBLB502 and anti-cermide antibody appear to be promising. Ex-RAD has been shown to have both radioprotective and radiomitigative properties. Ex-RAD protects the hematopoietic system and is able to increase survival of irradiated mice by alleviating the severe radiation induced pancytopenia and restoring select bone marrow functions through the up-regulation of the PI3-kinase/AKT pathways and pathways involved with the DNA damage response and DNA repair. Ex-RAD studies have received significant funding from DMRDP (DoD) and BARDA (HHS).
My lab is also working to develop GT3, as a radiation countermeasure in collaboration with Prof. Martin Hauer-Jensen. It has shown great promise in rodent model, capable of mobilizing progenitors, and its radioprotective efficacy is mediated through G-CSF in murine model. Recently, we found that a single administration of GT3, without additional support (fluids, antibiotics, blood products, etc.), was just as effective as multiple administrations of G-CSF, the current gold standard of radiation countermeasures approved by US FDA, with full support. Based on the promising results of our pilot study using the large animal model, we have received funding from CDMRP (DoD) for the advanced development of GT3.
Additionally, we are working to develop a novel anti-ceramide antibody in collaboration with Prof. Richard Kolesnick of Sloan Kettering and Ceramide Theraprutics as a radiation countermeasure, capable of being administered prior to or after radiation exposure. Studies have indicated that this potential countermeasure inhibits ceramide-mediated endothelial apoptosis, which provides significant protection against radiation induced, potentially fatal, gastrointestinal syndrome. Additional studies have shown that a single chain variable fragment of the full length antibody molecule is effective in doses one tenth of the full length version. This project had been supported by DMRDP (DoD). Additional countermeasures being investigated are CBLB612, CBLB613, and myeloid progenitors in collaboration with various academic and corporate partners with support from various funding agencies such as BARDA, NIAID, JPC7, CDMRP, and DMRDP.
My laboratory focuses attention on the molecular basis of radiation injury which results in acute radiation syndromes (ARS), and the mechanism of action of potential radiation countermeasures. Our ultimate goal is to develop radiation countermeasures to protect military personnel, first responders and civilians from succumbing to ARS following radiation exposure whether it is accidental or as a result of deliberate attack. To achieve this goal we are currently investigating the mechanism of action of gamma-tocotrienol (GT3, an isomer of Vitamin E), Ex-RAD (a chlorobenzylsulphone derivative), toll-like receptor (TLR) ligands (CBLB502), and anti-ceramide antibody at the cellular level, by evaluating cell signaling pathways (cytokine expression, p53 pathway, TLR activation) including DNA damage and repair pathways.
In collaboration with corporate partners, my lab is developing several radiation countermeasures which are under advanced stages of development. CBLB502 and anti-cermide antibody appear to be promising. Ex-RAD has been shown to have both radioprotective and radiomitigative properties. Ex-RAD protects the hematopoietic system and is able to increase survival of irradiated mice by alleviating the severe radiation induced pancytopenia and restoring select bone marrow functions through the up-regulation of the PI3-kinase/AKT pathways and pathways involved with the DNA damage response and DNA repair. Ex-RAD studies have received significant funding from DMRDP (DoD) and BARDA (HHS).
My lab is also working to develop GT3, as a radiation countermeasure in collaboration with Prof. Martin Hauer-Jensen. It has shown great promise in rodent model, capable of mobilizing progenitors, and its radioprotective efficacy is mediated through G-CSF in murine model. Recently, we found that a single administration of GT3, without additional support (fluids, antibiotics, blood products, etc.), was just as effective as multiple administrations of G-CSF, the current gold standard of radiation countermeasures approved by US FDA, with full support. Based on the promising results of our pilot study using the large animal model, we have received funding from CDMRP (DoD) for the advanced development of GT3.
Additionally, we are working to develop a novel anti-ceramide antibody in collaboration with Prof. Richard Kolesnick of Sloan Kettering and Ceramide Theraprutics as a radiation countermeasure, capable of being administered prior to or after radiation exposure. Studies have indicated that this potential countermeasure inhibits ceramide-mediated endothelial apoptosis, which provides significant protection against radiation induced, potentially fatal, gastrointestinal syndrome. Additional studies have shown that a single chain variable fragment of the full length antibody molecule is effective in doses one tenth of the full length version. This project had been supported by DMRDP (DoD). Additional countermeasures being investigated are CBLB612, CBLB613, and myeloid progenitors in collaboration with various academic and corporate partners with support from various funding agencies such as BARDA, NIAID, JPC7, CDMRP, and DMRDP.
Representative publications, projects, and/or deployments
- G1B23687 Determination of radiation dose response for the AFRRI LINAC and subsequent non-clinical studies to evaluate potential medical countermeasures as mitigators of hematopoietic and/or low dose GI syndromes (H-ARS; GI-ARS) in an NHP model. Biomedical Advanced Research and Development Authority (BARDA), $8,535,865, September 15, 2015 – September 14, 2019
- G1B22927 Advanced development of gamma-tocotrienol as a radiation countermeasure. Congressionally Directed Medical Research Programs (CDMRP), $7,811,978, September 21, 2015 – September 20, 2019.
- G2B2HF Evaluation of radiation mitigators in nonhuman primates with supportive care. National Institute of Allergy and Infectious Diseases (NIAID), FY 2016 $406,581, FY 2017 $1,264,698, September 2015 – Sepetember 2017, Open ended, yearly renewal expected every year with additional budget.
- NAB22586 Advanced development of Ex-RAD as a radiomitigator. Defense Medical Research and Development Program (DMRDP), $ 1,198,000, April 2014 – September 2017
- G1B24024 Advanced Development of BIO 300 for Acute Radiation Syndrome and Delayed Effects of Acute Radiation Exposure, Congressionally Directed Medical Research Programs (CDMRP), $1,195,189, October 2016 – September 2019
- RAB24402 Biomarkers for radiation injury: Integrative omics study, AFRRI, $240,000, November 11, 2016 – September 30, 2019
- AFR-B2-4365 Development of Bio 301: An encapsulated nano-genistein therapy, Congressionally Directed Medical Research Programs (CDMRP), $712,295, POP to be negotiated
Bibliography
Biosketch Link:
- Singh VK, Seed TM: A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: Part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures. Int J Radiat Biol (in press: DOI: 10.1080/09553002.2017.1332438), 2017.
- Singh VK, Garcia M, Seed TM: A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: Part II. Countermeasures for limited indications, internalized radionuclides, emesis, late effects, and agents demonstrating efficacy in large animals with or without FDA IND status. Int J Radiat Biol (in press: DOI: 10.1080/09553002.2017.1338782), 2017.
- Singh VK, Hanlon BK, Santiago PT, Seed TM: A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: Part III. Countermeasures under early stages of development along with ‘standard of care’ medicinal and procedures not requiring regulatory approval for use. Int J Radiat Biol (in press: DOI: 10.1080/09553002.2017.1332440), 2017.
- Fendler W, Malachowska B, Meghani K, Konstantinopoulos PA, Guha C, Singh VK, Chowdhury C: Evolutionarily conserved serum microRNAs can predict radiation-induced fatality in non-human primates. Sci Transl Med 9:eaal2408, 2017
- Singh VK, Fatanmi OO, Wise SY, Newman VL, Romaine PLP, Seed TM: The potentiation of the radioprotective efficacy of two medical countermeasures, gamma-tocotrienol and amifostine, by a combination prophylactic modality. Radiat Prot Dosimetry 172:302-310, 2016.
- Singh VK, Kulkarni S, Fatanmi OO, Wise SY, Newman VL, Romaine PLP, Hendrickson H, Gulani J, Ghosh SP, Kumar KS, Hauer-Jensen M: Radioprotective efficacy of gamma-tocotrienol in nonhuman primates. Radiat Res 185:285-298, 2016.
- Krivokrysenko VI, Toshkov I, Gleiberman A, Krasnov P, Shyshynova I, Bespalov I, Maitra R, Narizhneva N, Singh VK, Whitnall MH, Purmal A, Shakhov A, Gudkov A, Feinstein E: TLR5 agonist Entolimod mitigates acute radiation syndrome in non-human primates. PLoS One 10:e0135388, 2015.
- Elliott TB, Bolduc DL, Ledney GD, Kiang JG, Fatanmi OO, Wise SY, Romaine PLP, Newman VL, Singh VK: Combined immunomodulator and antimicrobial therapy eliminates polymicrobial sepsis and modulates cytokine production in mice exposed to radiation and combined injury. Int J Radiat Biol 91:690-702, 2015.
- Dalgard CL, Jacobowitz DM, Singh VK, Saleem KS, Ursano RJ, Starr JM, Pollard HB: A novel analytical brain block tool to enable functional annotation of discriminatory transcript biomarkers among discrete regions of the fronto-limbic circuit in primate brain. Brain Res 1600:42-58, 2015.
- Singh VK, Wise SY, Fatanmi OO, Scott J, Romaine PLP, Newman VL, Verma A, Elliott TB, Seed TM: Progenitors mobilized by gamma-tocotrienol as an effective radiation countermeasure. PLoS ONE 9:e114078, 2014.
PHA - National Faculty
Brian M. Cox, Ph.D.
Name: Brian M. Cox, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Professor of Pharmacology & Neuroscience
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Neuropharmacology - opiate drugs & substance use disorderds
Traumatic brain injury - mechanisms & biomarkers
Email:
Office Phone:
(301) 295-3260
Education
Ph.D. in Pharmacology, St. Mary's Hospital Medical School, University of London, London, United Kingdom, 1965
B.Sc. in Pharmacolopy, Chelsea College of Science & Technology, University of London, London, United Kingdom, 1962
B.Sc. in Pharmacolopy, Chelsea College of Science & Technology, University of London, London, United Kingdom, 1962
Biography
Dr. Cox is currently Professor of Pharmacology and Neuroscience at the Uniformed Services University (USU) in Bethesda MD. He received his initial training in pharmacology from Chelsea College of Science and Technology in London, UK, and received a Ph.D. in Pharmacology from St. Mary's Hospital Medical School, University of London, UK. After teaching pharmacology to pharmacy and science students at Chelsea College of Science and Technology of the University of London for eight years, he became a visiting scientist in the Department of Pharmacology at Stanford University, and was appointed Consulting Associate Professor of Pharmacology at Stanford in 1978. Concurrently, he served as Laboratory Research Group Director and then Associate Director for Research for the Addiction Research Foundation in Palo Alto, CA. In 1981, Dr. Cox moved to his current position at USU, where he served as chair of the Department of Pharmacology from 1995 until 2007. He currently also serves as an Assistant Dean for Graduate Education at USU.
For most of his career Dr. Cox's research has focused on characterizing the receptors utilized by opiate drugs and their endogenous ligands, and in defining potential physiological and pathophysiological roles for endogenous opioids and other neuropeptides. His lab is currently studying factors affecting peptide and receptor expression, and changes at the cellular level induced by drugs of abuse, severe stress, or neural injury. He now leads the Biomarkers Group of the USU/NIH Center for Neuroscience and Regenerative Medicine, evaluating neurochemical mechanisms underlying traumatic brain injury and potential biomarkers for TBI.
Dr. Cox has been a member of the American Society for Pharmacology and Experimental Therapeutics (ASPET) since 1976. He served as Secretary/Treasurer of (1997-2000), and was elected President of ASPET for 2009-2010. He chaired the ASPET Board of Publications Trustees from 2002-2007. He has served on the Editorial Boards of the Journal of Pharmacology and Experimental Therapeutics (1998 – present), Molecular Pharmacology (1981-1994), and Molecular Interventions (2000-2002). Dr. Cox was a member of the ASPET Scientific Program Committee from 1986-1990 and Chaired the Program Committee from 1990-1996. He served as ASPET’s representative to the Experimental Biology Program Committee from 1991-1994 and served on the Experimental Biology Board from 1996-1999 (as Chairman for 1998-1999). He is currently serving a second term as a member of the Board of Directors of the Federation of American Societies of Experimental Biology.
Dr. Cox was the ASPET representative to the International Advisory Committee for the 1998 International Union of Pharmacology (IUPHAR) Congress in Munich, Germany, and chaired the IUPHAR World Congress of Pharmacology Scientific Program Committee for the 2002 meeting, held in San Francisco, CA. He is also a member of the British Pharmacological Society, the Society for Neuroscience, the AAAS, the American Society for Neurochemistry, and the International Narcotics Research Conference (for which he served as President from 1994-1998).
For most of his career Dr. Cox's research has focused on characterizing the receptors utilized by opiate drugs and their endogenous ligands, and in defining potential physiological and pathophysiological roles for endogenous opioids and other neuropeptides. His lab is currently studying factors affecting peptide and receptor expression, and changes at the cellular level induced by drugs of abuse, severe stress, or neural injury. He now leads the Biomarkers Group of the USU/NIH Center for Neuroscience and Regenerative Medicine, evaluating neurochemical mechanisms underlying traumatic brain injury and potential biomarkers for TBI.
Dr. Cox has been a member of the American Society for Pharmacology and Experimental Therapeutics (ASPET) since 1976. He served as Secretary/Treasurer of (1997-2000), and was elected President of ASPET for 2009-2010. He chaired the ASPET Board of Publications Trustees from 2002-2007. He has served on the Editorial Boards of the Journal of Pharmacology and Experimental Therapeutics (1998 – present), Molecular Pharmacology (1981-1994), and Molecular Interventions (2000-2002). Dr. Cox was a member of the ASPET Scientific Program Committee from 1986-1990 and Chaired the Program Committee from 1990-1996. He served as ASPET’s representative to the Experimental Biology Program Committee from 1991-1994 and served on the Experimental Biology Board from 1996-1999 (as Chairman for 1998-1999). He is currently serving a second term as a member of the Board of Directors of the Federation of American Societies of Experimental Biology.
Dr. Cox was the ASPET representative to the International Advisory Committee for the 1998 International Union of Pharmacology (IUPHAR) Congress in Munich, Germany, and chaired the IUPHAR World Congress of Pharmacology Scientific Program Committee for the 2002 meeting, held in San Francisco, CA. He is also a member of the British Pharmacological Society, the Society for Neuroscience, the AAAS, the American Society for Neurochemistry, and the International Narcotics Research Conference (for which he served as President from 1994-1998).
Representative publications, projects, and/or deployments
- Assistant Dean for Graduate Education, Uniformed Services University, Bethesda MD 20814, since 2014
- Director, Biospecimen Repository, Center for Neuroscience & Regenerative Medicine, Uniformed Services University, Bethesda MD 20814, since 2009
- Professor of Pharmacology, Uniformed Services University, Bethesda MD 20814, since 1981
- Associate Director for Research, Addiction Research Foundation, Stanford, California, 94305, 1977-1981
- Consulting Associate Professor of Pharmacology, Stanford University, Stanford CA, 94305. 1978 - 1981
- Research Associate, Director, Laboratory Research Group, Addiction Research Foundation, Stanford, California, 94305, 1973-1977
- Lecturer (British System) in Pharmacology, Chelsea College, University of London, London, United Kingdom, 1965-1973
- Nicholas Research Fellow, St. Mary's Hospital Medical School, University of London, London, United Kingdom, 1962-1965
Bibliography
- Cox, B.M. and Weinstock, M. Quantitative studies of the antagonism by nalorphine of some of the actions of morphine-like analgesic drugs. Br. J. Pharmac. 22:289-300, 1964.
- Cox, B.M. and Osman, O.H. Inhibition of the development of tolerance to morphine in rats by drugs which inhibit ribonucleic acid or protein synthesis. Br. J. Pharmac. 38:157-170, 1970.
- Cox, B.M., Opheim, K., Teschemacher, H.-J. and Goldstein, A. A peptide-like substance from pituitary that acts like morphine. 2. Purification and properties. Life Sci. 16:1777-1782, 1975.
- Goldstein, A., Cox, B.M., Klee, W.A., and Nirenberg, M. Endorphin from pituitary inhibits cyclic AMP formation in homogenates of neuroblastoma X glioma hybrid cells. Nature 265:362-363, 1977.
- Whitnall, M.H., Gainer, H., Cox, B.M. and Molineaux, C.J. Dynorphin A(1-8) is contained within vasopressin neurosecretory vasicles in rat pituitary. Science 222:1137-1139, 1983.
- Faden, A.I., Molineaux, C.J., Rosenberger, J.G., Jacobs, T.P. and Cox, B.M. Endogenous opioid immunoreactivity in rat spinal cord following traumatic injury. Ann. Neurol. 17:386-390, 1985.
- Werling, L.L., Puttfarcken, P.S. and Cox, B.M. Multiple agonist-affinity states of opioid receptors: regulation of binding by guanyl nucleotides in guinea pig cortical, NG108-15, and 7315c cell membranes. Mol. Pharmacol. 33:423-431, 1988.
- Marti M, Mela F, Fantin M, Zucchini S, Brown JM, Witta J, Di Benedetto M, Buzas B, Reinscheid RK, Salvadori S, Guerrini R, Romualdi P, Candeletti S, Simonato M, Cox BM and Morari M. Blockade of nociceptin/orphanin FQ transmission attenuates symptoms and neurodegeneration associated with Parkinson’s disease. J. Neuroscience 25: 9591-9601, 2005.
- Authement ME, Kodangatil JN, Gouty S, Rusnak M, Symes AJ, Cox BM, Nugent F. Histone deacetylase inhibition rescues maternal deprivation-induced GABAergic metaplasticity through restoration of AKAP signaling. Neuron 86: 1240-1252, 2015.
- Authement M, Kassis H, Langlois L, Gouty S, Dacher M, Sheopard R, Cox BM & Nugent FS. Morphine-induced synaptic abnormalities in the VTA are reversed by HDAC inhibition. J. Neurophysiol. 116(3): 1093-1103, 2016.
Regina M Day, Ph.D.
Name: Regina M Day, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Vice Chair
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Email:
Office Phone:
(301) 295-3236
Education
A.B. Smith College, Northampton, MA, USA
Ph.D. Tufts University, Boston, MA, USA
Ph.D. Tufts University, Boston, MA, USA
Ying-Hong Feng, M.D., Ph.D
Name: Ying-Hong Feng, M.D., Ph.D
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Dr.
Faculty Rank:
Associate Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Receptor structure-function & signaling; Epigenome editing & transcription regulation
Translational research in neurodegenerative diseases, mood disorder, cancer, diabetes, and cardiovascular diseases
Email:
Office Phone:
(301) 295-3232
Department Website:
Education
1978-1983, M.D., Wuhan University School of Medicine, Wuhan, China
1990-1994, Ph.D., Biochemistry, University of Oxford, Oxford, UK
1994-1997, Postdoctoral, Molecular Cardiology, Cleveland Clinic Foundation
1990-1994, Ph.D., Biochemistry, University of Oxford, Oxford, UK
1994-1997, Postdoctoral, Molecular Cardiology, Cleveland Clinic Foundation
Biography
Feng’s lab has three research programs. The first is about crosstalk signaling of receptors in the form of receptor dimerization in pathophysiology such as vascular inflammation, metabolism (type 2 diabetes), pain (silent myocardial ischemia), depression, immunosuppression, cancer progression, and etc. The second is about translational research on neurodegenerative diseases and cancer with focus on novel splicing variants, of critical genes that are known to play an important role in depression, neurodegeneration, neuroregeneration, exosome biology, tumorigenesis, and cancer progression. The last is to develop novel technologies for genome editing and epigenome editing.
Representative publications, projects, and/or deployments
- Feng YH, Li X, Zeng R, Gorodeski GI. Endogenously Expressed Truncated P2X7 Receptor Lacking the C-Terminus is Preferentially Upregulated in Epithelial Cancer Cells and Fails to Mediate Ligand-Induced Pore Formation and Apoptosis. Nucleosides Nucleotides Nucleic Acids. 25:1271-6 (2006)
- Feng YH, Li X, Zeng R, Gorodeski GI. Endogenously expressed truncated P2X7 receptor lacking the C-terminus is preferentially upregulated in epithelial cancer cells and fails to mediate ligand-induced pore formation and apoptosis. Nucleosides Nucleotides Nucleic Acids. 25(9-11):1271-6 (2006)
- Chen M, Wang T, Liao ZX, Pan XL, Feng YH, Wang H. Nicotine-induced prenatal overexposure to maternal glucocorticoid and intrauterine growth retardation in rat. Exp Toxicol Pathol. 59: 245-51 (2007)
- 30. Zhang X, Wang G, Dupre DJ, Feng Y, Robitaille M, Lazartigues E, Feng YH, Hebert TE, Wu G. Rab1 GTPase and dimerization in the cell surface expression of angiotensin II type 2 receptor. J Pharmacol Exp Ther. 330(1):109-17 (2009)
- 31. Guo J, Li ZC and Feng YH. Expression and activation of the reprogramming transcription factors. Biochem Biophys Res Commun. 390(4):1081-6 (2009)
- 32. Zhang J, Villacorta L, Chang L, Fan Z, Hamblin M, Zhu T, Chen CS, Cole MP, Schopfer FJ, Deng CX, Garcia-Barrio MT, Feng YH, Freeman BA, Chen YE. Nitrated oleic acid inhibits Angiotensin II-induced hypertension. Circ Res, 107(4):540-8 (2010)
- 34. Day RD, Lee YH, Han L, Kim YC, Feng YH. Angiotensin II activates AMPK for execution of apoptosis through energy-dependent and -independent mechanisms. Am J Physiol Lung Cell Mol Physiol, 301(5):L772-81 (2011)
- 35. Wang TT, Chen M, Liu L, Cheng H, Yan YE, Feng YH*, Wang H. Nicotine induces a single CpG methylation in the StAR promoter: a potential mechanism for reduced StAR expression and cortisol production. Toxicol and Applied Pharmacol. 257(3):328-37 (2011) *Co-senior author
- 37. Wang H, Yin H, Yan F, Sun M, Du L, Peng W, Li Q, Feng Y, Zhou Y. Folate-mediated mitochondrial targeting with doxorubicin-polyrotaxane nanoparticles overcomes multidrug resistance. Oncotarget. 6(5):2827-42 (2015).
- 38. Li K, Pang J, Cheng H, Wei-Peng Liu WP, Chen MK, Yun Luo Y, Di JM, Zhang H, Huang WT, Li LY, Shao CK, Feng YH*, Gao X. Manipulation of prostate cancer metastasis by locus-specific modification of the CRMP4 promoter region using chimeric TALE DNA methyltransferase and demethylase. Oncotarget. 6(12):10030-44 (2015) *Co-senior author
Bibliography
- Feng YH, Saad Y and Karnik SS. Reversible Inactivation of AT2 Angiotensin II Receptor from Cysteine-Disulfide Bond Exchange. FEBS Letters 484, 133-138 (2000)
- Feng YH, Sun Y, and Douglas JG. G??-Independent Constitutive Association of Gs? with SHP-1 and Angiotensin II Receptor AT2 Is Essential in AT2-mediated Activation of SHP-1. Proc. Natl. Acad. Sci. USA 99:12049-12054 (2002)
- Wang Q, Li X, Wang L, Feng YH, Zeng R, Gorodeski GI. Anti-apoptotic effects of estrogen in normal and in cancer human cervical epithelial cells. Endocrinology 145:5568-79 (2004)
- Wang Q, Wang L, Feng YH, Li X, Zeng R, Gorodeski GI. P2X7-receptor-mediated apoptosis of human cervical epithelial cells. Am J Physiol Cell Physiol. 287:C1349-58 (2004)
- Wang L, Feng YH, Gorodeski GI. EGF facilitates epinephrine inhibition of P2X7-receptor pore formation by modulating 2-adrenoceptor internalization and recycling: a signaling network. Endocrinology 146:164-74 (2005)
- Feng YH, Zhou LY, Sun Y, and Douglas JG. Functional Diversity of AT2 Receptor Orthologues in Closely related Eutherian. Kidney Intl 67:1731-8 (2005)
- eng YH, Wang L, Wang Q, Li X, Zeng R, Gorodeski GI. ATP ligation stimulates GRK-3 - mediated phosphorylation and -arrestin-2- and dynamin-dependent internalization of the P2X7-receptor. Am J Physiol Cell Physiol. 288:C1342-56 (2005)
- Feng YH, Zhou L, Qiu R, and Robin Zeng. Single mutations at Asn295 and Leu305 in the cytoplasmic half of TM7 of the AT1 receptor induce promiscuous agonist specificity for angiotensin II fragments - A PSEUDO-CONSTITUTIVE ACTIVITY. Mol Pharmacol 68:347-55 (2005)
- Feng YH, Ding Y, Ren S, Xu C, Karnik SS. Unconventional homologous internalization of the AT1 receptor induced by G protein-independent signals. Hypertension 46:419-25 (2005)
- Feng YH, Li X, Wang L, Zhou L, Gorodeski GI. A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization. J Biol Chem. 281:17228-37 (2006)
Sergey Iordanskiy, Ph.D.
Name: Sergey Iordanskiy, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Assistant Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Molecular biology of retroviruses and host genomes; Effect of cellular stress on virus latency and replication; Exosomes in intercellular communication and cytopathogenesis.
Lentiviral vectors for delivery and expression of genome editing tools; Coinfection of HIV and human blood parasites.
Email:
Office Phone:
(301) 295-0580
Department Website:
Education
B.S & M.S., Biochemistry, Moscow State University of Education, Moscow, Russia
Ph.D., Cellular Biology, Moscow State University of Education & Ivanovsky Research Institute of Virology, Russian Academy of Medical Sciences
Postdoctoral Training, Molecular Biology of AIDS, Picower Institute for Medical Research, Manhasset, NY
Postdoctoral Training, Molecular Virology, George Washington University, Washington, DC
Ph.D., Cellular Biology, Moscow State University of Education & Ivanovsky Research Institute of Virology, Russian Academy of Medical Sciences
Postdoctoral Training, Molecular Biology of AIDS, Picower Institute for Medical Research, Manhasset, NY
Postdoctoral Training, Molecular Virology, George Washington University, Washington, DC
Biography
RESEARCH INTERESTS
Radiation-induced cellular stress and human endogenous retroviruses
Human endogenous retroviruses (HERVs) constitute from 5 to 9% of human genome. Most of integrated HERV genomes are silenced. However, detection of high levels of HERV-K mRNA, proteins, and even virions in a wide range of cancers suggests that some HERVs may play an essential role in cancer development. HERV-K subgroup HML-2 is involved into the activation of various types of cancer. Recent studies revealed dramatic increase of HERV-K and -R transcription in the prostate, breast and colon cancer after standard doses of radiotherapy. Our studies of the effect of radiation doses used for cancer therapy on the cells latently-infected with another retrovirus, HIV-1, in the context of HIV-related cancer, revealed inappropriate entry and arrest at S phase of the cell cycle, induction of viral transcription and enhanced apoptotic response predominantly in the infected cells. We examine pathogenic effect of integrated retroviruses in the cells, exposed to different irradiation doses, including X-ray and gamma doses used for cancer therapy and neutrons. We focus on the mechanism of activation of retroviral promoters, gene expression, translation and secretion of HERV proteins using chromatin immunoprecipitation, transcriptomic and proteomic analysis. Important part of our study is analysis of the impact of extracellular viral RNA, proteins and likely released HERV virions on unexposed cells. Another aspect of our study is testing of key HERV RNA and proteins for their potential to be used as biomarkers of different radiation doses. Our ultimate goal is to determine retrovirus-mediated side effects of radiotherapeutic treatment and environmental radiation and to find prospective targets and interventions to counteract this influence.
Exosomes in cytopathogenesis and intercellular communications within context of radiation-induced stress.
Initially small extracellular vesicles, exosomes, were thought to be a mechanism for discarding unwanted cellular material. However, in recent years, numerous evidence has indicated the role of exosomes in intercellular communication and the progression of various pathologies, including cancer and multiple neurodegenerative disorders. Exosomes are cell-derived vesicles that are present in all biological fluids and are capable of carrying RNAs and proteins which can be exchanged from cell-to-cell. Existing data indicate that exosomes and their cargo play crucial roles in communicating of radiation-induced and bystander cells with the result related to DNA damage and cell pathogenesis. We recently demonstrated multiple pathogenic effects of exosomes from the cells containing integrated retroviral genomes, such as human T lymphotropic virus 1 (HTLV-1) and HIV-1 on naïve cells. These effects were enhanced by the exposure of producing cells to ionizing radiation. Current research in our laboratory is focused on the analysis of host-cellular and viral cargo in the exosomes released from the radiation-exposed cells. We also investigate how non radiation-exposed cells respond to exosome-mediated effect of radiation in the context of radiotherapy and environmental radiation. Potential outcomes include understanding of the functions of exosome-packaged micro- and mRNAs, viral and host proteins in recipient cells and their pathogenic impact that is related to radiation. Identification of exosome-incorporated biomarkers of radiation doses is also part of this study.
Collaborative Projects
Our laboratory is involved in collaborative projects with George Washington University (Paul Brindley Lab) and Massachusetts Institute of Technology (Kevin Esvelt Lab). These studies are related to coinfection of HIV and human blood fluke Schistosoma mansoni and S. hematobium and the use of HIV-based lentiviral vectors for delivery of gene editing tools within the context of Gene Drive strategy.
Radiation-induced cellular stress and human endogenous retroviruses
Human endogenous retroviruses (HERVs) constitute from 5 to 9% of human genome. Most of integrated HERV genomes are silenced. However, detection of high levels of HERV-K mRNA, proteins, and even virions in a wide range of cancers suggests that some HERVs may play an essential role in cancer development. HERV-K subgroup HML-2 is involved into the activation of various types of cancer. Recent studies revealed dramatic increase of HERV-K and -R transcription in the prostate, breast and colon cancer after standard doses of radiotherapy. Our studies of the effect of radiation doses used for cancer therapy on the cells latently-infected with another retrovirus, HIV-1, in the context of HIV-related cancer, revealed inappropriate entry and arrest at S phase of the cell cycle, induction of viral transcription and enhanced apoptotic response predominantly in the infected cells. We examine pathogenic effect of integrated retroviruses in the cells, exposed to different irradiation doses, including X-ray and gamma doses used for cancer therapy and neutrons. We focus on the mechanism of activation of retroviral promoters, gene expression, translation and secretion of HERV proteins using chromatin immunoprecipitation, transcriptomic and proteomic analysis. Important part of our study is analysis of the impact of extracellular viral RNA, proteins and likely released HERV virions on unexposed cells. Another aspect of our study is testing of key HERV RNA and proteins for their potential to be used as biomarkers of different radiation doses. Our ultimate goal is to determine retrovirus-mediated side effects of radiotherapeutic treatment and environmental radiation and to find prospective targets and interventions to counteract this influence.
Exosomes in cytopathogenesis and intercellular communications within context of radiation-induced stress.
Initially small extracellular vesicles, exosomes, were thought to be a mechanism for discarding unwanted cellular material. However, in recent years, numerous evidence has indicated the role of exosomes in intercellular communication and the progression of various pathologies, including cancer and multiple neurodegenerative disorders. Exosomes are cell-derived vesicles that are present in all biological fluids and are capable of carrying RNAs and proteins which can be exchanged from cell-to-cell. Existing data indicate that exosomes and their cargo play crucial roles in communicating of radiation-induced and bystander cells with the result related to DNA damage and cell pathogenesis. We recently demonstrated multiple pathogenic effects of exosomes from the cells containing integrated retroviral genomes, such as human T lymphotropic virus 1 (HTLV-1) and HIV-1 on naïve cells. These effects were enhanced by the exposure of producing cells to ionizing radiation. Current research in our laboratory is focused on the analysis of host-cellular and viral cargo in the exosomes released from the radiation-exposed cells. We also investigate how non radiation-exposed cells respond to exosome-mediated effect of radiation in the context of radiotherapy and environmental radiation. Potential outcomes include understanding of the functions of exosome-packaged micro- and mRNAs, viral and host proteins in recipient cells and their pathogenic impact that is related to radiation. Identification of exosome-incorporated biomarkers of radiation doses is also part of this study.
Collaborative Projects
Our laboratory is involved in collaborative projects with George Washington University (Paul Brindley Lab) and Massachusetts Institute of Technology (Kevin Esvelt Lab). These studies are related to coinfection of HIV and human blood fluke Schistosoma mansoni and S. hematobium and the use of HIV-based lentiviral vectors for delivery of gene editing tools within the context of Gene Drive strategy.
Bibliography
Biosketch Link:
- Suttiprapa S, Rinaldi G, Tsai IJ, Mann VH, Dubrovsky L, Yan HB, Holroyd N, Huckvale T, Durrant C, Protasio AV, Pushkarsky T, Iordanskiy S, Berriman M, Bukrinsky MI and PJ Brindley, HIV-1 Integrates Widely throughout the Genome of the Human Blood Fluke Schistosoma mansoni. PLoS Pathog. 2016 Oct 20;12(10):e1005931.
- Santos S, Obukhov Y, Nekhai S, Pushkarsky T, Brichacek B, Bukrinsky M and S Iordanskiy. Cellular minichromosome maintenance complex component 5 (MCM5) is incorporated into HIV-1 virions and modulates viral replication in the newly infected cells, Virology. 2016 Oct;497:11-22.
- Iordanskiy S and F Kashanchi, Potential of radiation-induced cellular stress for reactivation of latent HIV-1 and killing of infected cells. AIDS Res Hum Retroviruses. 2016 32(2):120-124.
- Sampey G, Saifuddin M, Schwab A, Barclay R, Punya S, Chung M-Y, Hakami RM, Asad Zadeh M, Lepene B, Klase ZA, El-Hage N, Young M, Iordanskiy S and F Kashanchi, Exosomes from HIV-1 infected cells stimulate production of pro-inflammatory cytokines through TAR RNA. J Biol Chem. 2016 291(3):1251-1266.
- Iordanskiy S, Van Duyne R, Sampey GC, Woodson CM, Fry K, Saifuddin M, Guo J, Wu Y, Romerio F and F Kashanchi, Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells. Virology 2015, 485:1–15.
- Guendel I, Iordanskiy S, Van Duyne R, Kehn-Hall K, Saifuddin M, Das R, Jaworski E, Sampey G, Senina S, Shultz L, Narayanan A, Chen H, Lepene B, Zeng C, and F. Kashanchi, Novel neuroprotective GSK-3β inhibitor restricts Tat-mediated HIV-1 replication. J Virol 2014, 88(2): 1189-1208
- Narayanan A, Iordanskiy S, Das R, Van Duyne R, Santos S, Jaworski E, Guendel I, Sampey G, Gerhart E, Iglesias-Ussel M, Popratiloff A, Hakami R, Kehn-Hall K, Young M, Subra C, Gilbert C, Bailey C, Romerio F and F. Kashanchi, Exosomes derived from HIV-1 infected cells contain TAR RNA. J Biol Chem. 2013 288(27): 20014-20033.
- Santos S, Obukhov Y, Nekhai S, Bukrinsky M and S Iordanskiy, Virus-producing cells determine the host protein profiles of HIV-1 virion cores. Retrovirology. 2012, 9:65.
- Iordanskiy S, Berro R, Altieri M, Kashanchi F. and M. Bukrinsky, Intracytoplasmic maturation of the human immunodeficiency virus type 1 reverse transcription complexes determines their capacity to integrate into chromatin. Retrovirology 2006. 3: 4
- Iordanskiy S, Zhao Y, DiMarzio P, Agostini I, Dubrovsky L, and M. Bukrinsky, Heat-shock protein 70 exerts opposing effects on Vpr-dependent and Vpr-independent HIV-1 replication in macrophages. Blood. 2004. 104: 1867-1872.
Robert L Kortum, M.D., Ph.D.
Name: Robert L Kortum, M.D., Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Assistant Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Cancer Cell Signaling
Ras
Email:
Office Phone:
(301) 295-3249
Department Website:
Education
Ph.D. - University of Nebraska Medical School, 2004
M.D. - University of Nebraska Medical School, 2006
M.D. - University of Nebraska Medical School, 2006
Bibliography
Biosketch Link:
Irwin Lucki, Ph.D.
Name: Irwin Lucki, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Professor and Chair
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Neuropharmacology
Antidepressant drugs
Email:
Office Phone:
(301) 295-3248
Education
Education: 1972 B.A. University of Illinois, Psychology
1976 M.A. University of Iowa, Psychology
1979 Ph.D. University of Iowa, Biopsychology
Postgraduate Training:
1979-1981 Postdoctoral Research Fellow, Psychopharmacology Training Program, Department of Psychiatry, University of Pennsylvania
1976 M.A. University of Iowa, Psychology
1979 Ph.D. University of Iowa, Biopsychology
Postgraduate Training:
1979-1981 Postdoctoral Research Fellow, Psychopharmacology Training Program, Department of Psychiatry, University of Pennsylvania
Biography
Selected from 180 publications:
Cryan, J.F., Valentino, R.J. and Lucki, I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neuroscience and Biobehavioral Reviews, 2005, 29:547-569.
Valentino, R.J., Lucki, I. and Van Bockstaele, E. Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction. Brain Research, 2010, 1314:29-37. PMC2819581
Ho, N., Sommers, M.S. and Lucki, I. Effects of diabetes on hippocampal neurogenesis: Links to cognition and depression. Neuroscience and Biobehavioral Reviews, 2013, 37:1346-1362. PMC3788092
Browne, C.A. and Lucki, I. Mechanisms mediating the antidepressant-like Lucki, I. The spectrum of behaviors influenced by serotonin. Biological Psychiatry, 1998, 44:151-162.
Page, M.E., Cryan, J.F., Sullivan, A., Dalvi, A. and Lucki, I. Behavioral and neurochemical effects of EMD 68843: A combined selective inhibitor of serotonin reuptake and partial 5-HT1A receptor agonist. Journal of Pharmacology and Experimental Therapeutics, 2002, 302:1-8.
Carr, G.V. and Lucki, I. The role of serotonin receptor subtypes in treating depression: A review of animal studies. Psychopharmacology, 2011, 213:265-287. PMC3374933
Carr, G.V., Schechter, L.E. and Lucki, I. Antidepressant and anxiolytic effects of
selective 5-HT6 receptor agonists in rats. Psychopharmacology, 2011, 213:499-507. PMC2910165
effects of ketamine: Screening for fast-acting novel antidepressants. Frontiers in Neuropharmacology, 2013, 4:161, 1-18. PMC3873522.
Mayorga, A.J., Dalvi, A., Page, M.E., Zimov-Levinson, S., Hen R. and Lucki, I. Antidepressant-like behavioral effects in 5-HT1A and 5-HT1B receptor mutant mice. Journal of Pharmacology and Experimental Therapeutics, 2001, 298:1101-1107.
Cryan, J.F., O’Leary, O.F., Jin, S.-H., Friedland, J.C., Ouyang, M., Hirsch, B.R., Page, M.E., Dalvi, A., Thomas, S.A. and Lucki, I. Norepinephrine deficient mice lack responses to antidepressant drugs, including SSRIs. Proceedings of the National Academy of Sciences, 2004, 101:8186-8191.
O’Leary, O.F., Bechtholt, A.J., Crowley, J.J., Valentino, R.J. and Lucki, I. The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs. European Neuropsychopharmacology, 2007, 17:215-226.
Balu, D.T., Turner, J.R., Brookshire, B.R., Hill, T.E., Blendy, J.A. and Lucki, I. Brain monoamines and responses to antidepressant drugs in MRL/MpJ versus C57BL/6J and mice. Neuropharmacology, 2013, 67:503-510. PMC437180
Cryan, J.F., Markou, A. and Lucki, I. Assessing antidepressant-like activity in laboratory animals: Recent developments and future needs. Trends in Pharmacological Sciences, 2002, 23(5): 238-245.
Crowley, J.J. and Lucki, I. Opportunities to discover genes regulating depression and antidepressant response from rodent behavioral genetics. Current Pharmaceutical Design, 11:157-169, 2005.
Bechtholt, A.J., Valentino, R.J. and Lucki, I. Overlapping and distinct brain regions associated
with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine. Neuropsychopharmacology, 2008, 33:2117-2130.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Price, M. L., Curtis, A.L., Kirby, L.G., Valentino, R.J. and Lucki, I. Biphasic effects of corticotropin-releasing factor on brain serotonergic activity. Neuropsychopharmacology, 1998, 18:492-502.
Price, M.L. and Lucki, I. Regulation of serotonin release in the lateral septum and striatum by corticotropin-releasing factor. Journal of Neuroscience, 2001, 21:2833-2841.
Howard, O., Carr, G.V., Hill, T.E., Valentino, R.J. and Lucki, I. Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin. Psychopharmacology, 2008, 199:569-82. PMC2744742
Snyder, K.P., Hill-Smith, T.E., Lucki, I. and Valentino, R.J. Corticotropin-releasing factor in the rat dorsal raphe nucleus promotes different forms of behavioral flexibility depending on social stress history. Neuropsychopharmacology, 2015, 40:2517-25. PMCID in process.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Falcon, E., Maier, K., Robinson, S.A. and Lucki, I. Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice. Psychopharmacology, 2015, 232:907-915. PMC4326609
Browne, C.A., van Nest, D. and Lucki, I. Antidepressant-like effects of buprenorphine in rats are strain dependent. Behavioural Brain Research, 2015, 278:385-392. PMC4382376
Falcon, E., Browne, C.A., Leon, R.M., Fleites, V.C., Sweeney, R., Kirby, L.G. and Lucki, I. Antidepressant-like effects of buprenorphine are mediated by kappa opioid receptors. Neuropsychopharmacology, 2016, 41(9):2344-2351. PMC4946065
A full bibliography of over 170 peer-reviewed publications is available at: http://www.ncbi.nlm.nih.gov/sites/myncbi/irwin.lucki.1/bibliography/45296221/public/?sort=date&direction=ascending.
Cryan, J.F., Valentino, R.J. and Lucki, I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neuroscience and Biobehavioral Reviews, 2005, 29:547-569.
Valentino, R.J., Lucki, I. and Van Bockstaele, E. Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction. Brain Research, 2010, 1314:29-37. PMC2819581
Ho, N., Sommers, M.S. and Lucki, I. Effects of diabetes on hippocampal neurogenesis: Links to cognition and depression. Neuroscience and Biobehavioral Reviews, 2013, 37:1346-1362. PMC3788092
Browne, C.A. and Lucki, I. Mechanisms mediating the antidepressant-like Lucki, I. The spectrum of behaviors influenced by serotonin. Biological Psychiatry, 1998, 44:151-162.
Page, M.E., Cryan, J.F., Sullivan, A., Dalvi, A. and Lucki, I. Behavioral and neurochemical effects of EMD 68843: A combined selective inhibitor of serotonin reuptake and partial 5-HT1A receptor agonist. Journal of Pharmacology and Experimental Therapeutics, 2002, 302:1-8.
Carr, G.V. and Lucki, I. The role of serotonin receptor subtypes in treating depression: A review of animal studies. Psychopharmacology, 2011, 213:265-287. PMC3374933
Carr, G.V., Schechter, L.E. and Lucki, I. Antidepressant and anxiolytic effects of
selective 5-HT6 receptor agonists in rats. Psychopharmacology, 2011, 213:499-507. PMC2910165
effects of ketamine: Screening for fast-acting novel antidepressants. Frontiers in Neuropharmacology, 2013, 4:161, 1-18. PMC3873522.
Mayorga, A.J., Dalvi, A., Page, M.E., Zimov-Levinson, S., Hen R. and Lucki, I. Antidepressant-like behavioral effects in 5-HT1A and 5-HT1B receptor mutant mice. Journal of Pharmacology and Experimental Therapeutics, 2001, 298:1101-1107.
Cryan, J.F., O’Leary, O.F., Jin, S.-H., Friedland, J.C., Ouyang, M., Hirsch, B.R., Page, M.E., Dalvi, A., Thomas, S.A. and Lucki, I. Norepinephrine deficient mice lack responses to antidepressant drugs, including SSRIs. Proceedings of the National Academy of Sciences, 2004, 101:8186-8191.
O’Leary, O.F., Bechtholt, A.J., Crowley, J.J., Valentino, R.J. and Lucki, I. The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs. European Neuropsychopharmacology, 2007, 17:215-226.
Balu, D.T., Turner, J.R., Brookshire, B.R., Hill, T.E., Blendy, J.A. and Lucki, I. Brain monoamines and responses to antidepressant drugs in MRL/MpJ versus C57BL/6J and mice. Neuropharmacology, 2013, 67:503-510. PMC437180
Cryan, J.F., Markou, A. and Lucki, I. Assessing antidepressant-like activity in laboratory animals: Recent developments and future needs. Trends in Pharmacological Sciences, 2002, 23(5): 238-245.
Crowley, J.J. and Lucki, I. Opportunities to discover genes regulating depression and antidepressant response from rodent behavioral genetics. Current Pharmaceutical Design, 11:157-169, 2005.
Bechtholt, A.J., Valentino, R.J. and Lucki, I. Overlapping and distinct brain regions associated
with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine. Neuropsychopharmacology, 2008, 33:2117-2130.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Price, M. L., Curtis, A.L., Kirby, L.G., Valentino, R.J. and Lucki, I. Biphasic effects of corticotropin-releasing factor on brain serotonergic activity. Neuropsychopharmacology, 1998, 18:492-502.
Price, M.L. and Lucki, I. Regulation of serotonin release in the lateral septum and striatum by corticotropin-releasing factor. Journal of Neuroscience, 2001, 21:2833-2841.
Howard, O., Carr, G.V., Hill, T.E., Valentino, R.J. and Lucki, I. Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin. Psychopharmacology, 2008, 199:569-82. PMC2744742
Snyder, K.P., Hill-Smith, T.E., Lucki, I. and Valentino, R.J. Corticotropin-releasing factor in the rat dorsal raphe nucleus promotes different forms of behavioral flexibility depending on social stress history. Neuropsychopharmacology, 2015, 40:2517-25. PMCID in process.
Carr, G.V., Bangasser, D.A., Bethea, T., Young, M., Valentino, R.J. and Lucki, I. Antidepressant-like effects of kappa opioid receptor antagonists in Wistar-Kyoto rats. Neuropsychopharmacology, 2010, 35(3):752-63. PMC2813986
Falcon, E., Maier, K., Robinson, S.A. and Lucki, I. Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice. Psychopharmacology, 2015, 232:907-915. PMC4326609
Browne, C.A., van Nest, D. and Lucki, I. Antidepressant-like effects of buprenorphine in rats are strain dependent. Behavioural Brain Research, 2015, 278:385-392. PMC4382376
Falcon, E., Browne, C.A., Leon, R.M., Fleites, V.C., Sweeney, R., Kirby, L.G. and Lucki, I. Antidepressant-like effects of buprenorphine are mediated by kappa opioid receptors. Neuropsychopharmacology, 2016, 41(9):2344-2351. PMC4946065
A full bibliography of over 170 peer-reviewed publications is available at: http://www.ncbi.nlm.nih.gov/sites/myncbi/irwin.lucki.1/bibliography/45296221/public/?sort=date&direction=ascending.
Representative publications, projects, and/or deployments
- 2007 - present, Principal Field Editor, Psychopharmacology
- 1995 - present, Editorial Advisory Board, Neuropsychopharmacology
- 2014 – present, Editorial Advisory Board, Neurobiology of Stress
- Buprenorphine for Depression and Anxiety.PI. NIMH, R01 MH92412, 2012-2018. Total direct costs = $1,250,000. The goal of this grant is to examine animal models supporting the development of buprenorphine for the clinical treatment of depression and anxiety.
- Kappa Receptor Antagonists as Rapid Acting Antidepressants. PI. NIMH, R01 MH105623, 2016-2020. Total direct costs = $1,000,000. The goal of this grant is to study animal models supporting the development of novel kappa receptor antagonists for the clinical treatment of mood disorders.
- Training Program in Neuropsychopharmacology. NIMH, T32 MH14654-34-38, 1978-2021. I was Training Program Director at the University of Pennsylvania 1992-2016.
- Regulation of Hippocampal Neurogenesis by Antidepressants. PI. NIMH, R01 MH86599, 2009-2015.
- Biology of Serotonin in Brain; Program Project Grant: Irwin Lucki, Ph.D., Program Director (1994-2007). NIMH, PO1-MH-48125.
- Regulation of Neurogenesis by Stress and Antidepressants. Program Director. National Cooperative Drug Discovery Group involving University of Pennsylvania and Wyeth Neuroscience. U01-MH 72832, 2005-2009.
Bibliography
- 2016- present Professor (with tenure) and Chair, Department of Pharmacology and Molecular Therapeutics, Uniformed University of the Health Sciences, Bethesda MD
- 2016-present Professor, Department of Psychiatry, Uniformed University of the Health Sciences, Bethesda MD
- 1996-2016 Professor of Psychology in Psychiatry (with tenure), Depts. of Psychiatry and Pharmacology, University of Pennsylvania, Philadelphia PA
- 1990-1996 Associate Professor of Psychology in Psychiatry (with tenure), Depts. of Psychiatry and Pharmacology, University of Pennsylvania, Philadelphia PA
- 1989-1990 Assistant Professor, Department of Pharmacology, University of Pennsylvania, Philadelphia PA
- 1984-1990 Assistant Professor of Psychology in Psychiatry, Department of Psychiatry, University of Pennsylvania, Philadelphia PA
- 1981-1984 Research Associate, Department of Psychiatry, University of Pennsylvania, Philadelphia PA
Fereshteh S. Nugent, Ph.D.
Name: Fereshteh S. Nugent, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
USU faculty
Faculty Rank:
Associate Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Synaptic plasticity, Reward Pathway, Addiction Neuorpsychiatric Disorders
Novel Anidepressants
Email:
Office Phone:
(301) 295-3243
Department Website:
Education
Ph.D., Neurophysiology, Tarbiat Modarres University, Tehran, Iran, 2003
Postdoctoral, Neuroscience, Brown University
Postdoctoral, Neuroscience, Brown University
Biography
Synaptic Plasticity of the Reward Pathway
Since the discovery of synaptic plasticity as the cellular correlate of learning and memory, strong overlaps between neural and cellular substrates of learning, drug addiction and stress-related disorders have been recognized. Yet it remains a major challenge to identify the neural circuits and synaptic mechanisms contributing to abnormalities in dopamine signaling induced by addictive drugs and adverse early life experiences. The major focus of my laboratory is the elucidation of synaptic mechanisms underlying reward learning, drug addiction and neuropsychiatric disorders such as depression, with particular emphasis on the midbrain dopamine system originating from the ventral tegmental area (VTA) and its control by the lateral habenula (LHb). Research in our laboratory also explores effects of severe early life stress on synaptic transmission and plasticity of distinct VTA dopamine circuits to identify the neural circuits and molecular mechanisms contributing to abnormalities in dopamine signaling induced by adverse early life experiences. To achieve these goals, we use a combination of immunohistochemical, biochemical, epigenetic, electrophysiological and behavioral techniques. We expect that identifying novel epigenetic mechanisms in the regulation of synaptic plasticity and memory formation in midbrain dopamine circuits will point to new directions in pharmacotherapy for drug addiction and stress-related disorders.
Selected Publications
Authement M.E., L. L. D., Shepard R.D., Browne C.A., Lucki L., Kassis H., Nugent F.S., A role for corticotrophin releasing factor signaling in the lateral habenula and its modulation by early life stress, Science Signaling, 11(520) (2018), Featured as the cover story
Summary: http://stke.sciencemag.org/cgi/content/summary/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Abstract: http://stke.sciencemag.org/cgi/content/abstract/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Reprint: http://stke.sciencemag.org/cgi/reprint/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Full text: http://stke.sciencemag.org/cgi/content/full/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Langlois, L.D. and Nugent F.S. Opiates and plasticity in ventral tegmental area, Invited Review, ACS Chemical Neuroscience, 20;8(9):1830-1838 (2017)
Authement M.E., Kodangattil J.N.,Gouty,S., Rusnak, M., Symes A.J., Cox B.M., and Nugent F.S., Histone deacetylase inhibition rescues maternal deprivation-induced GABAergic metaplasticity through restoration of AKAP signaling, Neuron, 86: 1240–1252 (2015)
Kodangattil J.N., Dacher M.A., Authement, M.E. and Nugent F.S., Spike timing-dependent plasticity at GABAergic synapses in the Ventral tegmental area. Journal of Physiology, 591.19: 4699-710 (2013)
Dacher, M. A., Gouty, S., Dash, S., Cox, B.M., and Nugent, F.S., A-kinase anchoring protein-calcineurin signaling in long-term depression of GABAergic synapses, Journal of Neuroscience, 33:2650-60 (2013)
Nugent, F.S., Penick, E.C., Kauer, J.A., Opiates block long-term potentiation of GABAergic synapses. Nature, 466: 1086-1095 (2007)
Postdoctoral Fellows: Dr. Ludovic Langlois
Graduate Students: Ryan Shepard
Lab Alumni: Dr. Matthieu Dacher (Université Pierre et Marie Curie, France), Dr. Jayaraj N. Kodangattil, Dr. Haifa Kassis, Dr. Michael Authement (NIAAA) and Steven Dash
Since the discovery of synaptic plasticity as the cellular correlate of learning and memory, strong overlaps between neural and cellular substrates of learning, drug addiction and stress-related disorders have been recognized. Yet it remains a major challenge to identify the neural circuits and synaptic mechanisms contributing to abnormalities in dopamine signaling induced by addictive drugs and adverse early life experiences. The major focus of my laboratory is the elucidation of synaptic mechanisms underlying reward learning, drug addiction and neuropsychiatric disorders such as depression, with particular emphasis on the midbrain dopamine system originating from the ventral tegmental area (VTA) and its control by the lateral habenula (LHb). Research in our laboratory also explores effects of severe early life stress on synaptic transmission and plasticity of distinct VTA dopamine circuits to identify the neural circuits and molecular mechanisms contributing to abnormalities in dopamine signaling induced by adverse early life experiences. To achieve these goals, we use a combination of immunohistochemical, biochemical, epigenetic, electrophysiological and behavioral techniques. We expect that identifying novel epigenetic mechanisms in the regulation of synaptic plasticity and memory formation in midbrain dopamine circuits will point to new directions in pharmacotherapy for drug addiction and stress-related disorders.
Selected Publications
Authement M.E., L. L. D., Shepard R.D., Browne C.A., Lucki L., Kassis H., Nugent F.S., A role for corticotrophin releasing factor signaling in the lateral habenula and its modulation by early life stress, Science Signaling, 11(520) (2018), Featured as the cover story
Summary: http://stke.sciencemag.org/cgi/content/summary/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Abstract: http://stke.sciencemag.org/cgi/content/abstract/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Reprint: http://stke.sciencemag.org/cgi/reprint/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Full text: http://stke.sciencemag.org/cgi/content/full/sigtrans;11/520/eaan6480?ijkey=HdDvVlA/ZsP76&keytype=ref&siteid=sigtrans
Langlois, L.D. and Nugent F.S. Opiates and plasticity in ventral tegmental area, Invited Review, ACS Chemical Neuroscience, 20;8(9):1830-1838 (2017)
Authement M.E., Kodangattil J.N.,Gouty,S., Rusnak, M., Symes A.J., Cox B.M., and Nugent F.S., Histone deacetylase inhibition rescues maternal deprivation-induced GABAergic metaplasticity through restoration of AKAP signaling, Neuron, 86: 1240–1252 (2015)
Kodangattil J.N., Dacher M.A., Authement, M.E. and Nugent F.S., Spike timing-dependent plasticity at GABAergic synapses in the Ventral tegmental area. Journal of Physiology, 591.19: 4699-710 (2013)
Dacher, M. A., Gouty, S., Dash, S., Cox, B.M., and Nugent, F.S., A-kinase anchoring protein-calcineurin signaling in long-term depression of GABAergic synapses, Journal of Neuroscience, 33:2650-60 (2013)
Nugent, F.S., Penick, E.C., Kauer, J.A., Opiates block long-term potentiation of GABAergic synapses. Nature, 466: 1086-1095 (2007)
Postdoctoral Fellows: Dr. Ludovic Langlois
Graduate Students: Ryan Shepard
Lab Alumni: Dr. Matthieu Dacher (Université Pierre et Marie Curie, France), Dr. Jayaraj N. Kodangattil, Dr. Haifa Kassis, Dr. Michael Authement (NIAAA) and Steven Dash
Frank Shewmaker, Ph.D.
Name: Frank Shewmaker, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Assistant Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Email:
Office Phone:
(301) 295-3527
Vijay K. Singh, Ph.D.
Name: Vijay K. Singh, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Title:
Prof.
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Radiation Biology
Countermeasures
Email:
Office Phone:
(301) 295-2347
Department Website:
Education
1983 Ph.D., Central Drug Research Institute (KU), India
1978 M.Sc., Kanpur University, India
1975 B.Sc., Magadh University, India
1978 M.Sc., Kanpur University, India
1975 B.Sc., Magadh University, India
Biography
Mechanism of radiation injury and advanced development of radiation countermeasures
My laboratory focuses attention on the molecular basis of radiation injury which results in acute radiation syndromes (ARS), and the mechanism of action of potential radiation countermeasures. Our ultimate goal is to develop radiation countermeasures to protect military personnel, first responders and civilians from succumbing to ARS following radiation exposure whether it is accidental or as a result of deliberate attack. To achieve this goal we are currently investigating the mechanism of action of gamma-tocotrienol (GT3, an isomer of Vitamin E), Ex-RAD (a chlorobenzylsulphone derivative), toll-like receptor (TLR) ligands (CBLB502), and anti-ceramide antibody at the cellular level, by evaluating cell signaling pathways (cytokine expression, p53 pathway, TLR activation) including DNA damage and repair pathways.
In collaboration with corporate partners, my lab is developing several radiation countermeasures which are under advanced stages of development. CBLB502 and anti-cermide antibody appear to be promising. Ex-RAD has been shown to have both radioprotective and radiomitigative properties. Ex-RAD protects the hematopoietic system and is able to increase survival of irradiated mice by alleviating the severe radiation induced pancytopenia and restoring select bone marrow functions through the up-regulation of the PI3-kinase/AKT pathways and pathways involved with the DNA damage response and DNA repair. Ex-RAD studies have received significant funding from DMRDP (DoD) and BARDA (HHS).
My lab is also working to develop GT3, as a radiation countermeasure in collaboration with Prof. Martin Hauer-Jensen. It has shown great promise in rodent model, capable of mobilizing progenitors, and its radioprotective efficacy is mediated through G-CSF in murine model. Recently, we found that a single administration of GT3, without additional support (fluids, antibiotics, blood products, etc.), was just as effective as multiple administrations of G-CSF, the current gold standard of radiation countermeasures approved by US FDA, with full support. Based on the promising results of our pilot study using the large animal model, we have received funding from CDMRP (DoD) for the advanced development of GT3.
Additionally, we are working to develop a novel anti-ceramide antibody in collaboration with Prof. Richard Kolesnick of Sloan Kettering and Ceramide Theraprutics as a radiation countermeasure, capable of being administered prior to or after radiation exposure. Studies have indicated that this potential countermeasure inhibits ceramide-mediated endothelial apoptosis, which provides significant protection against radiation induced, potentially fatal, gastrointestinal syndrome. Additional studies have shown that a single chain variable fragment of the full length antibody molecule is effective in doses one tenth of the full length version. This project had been supported by DMRDP (DoD). Additional countermeasures being investigated are CBLB612, CBLB613, and myeloid progenitors in collaboration with various academic and corporate partners with support from various funding agencies such as BARDA, NIAID, JPC7, CDMRP, and DMRDP.
My laboratory focuses attention on the molecular basis of radiation injury which results in acute radiation syndromes (ARS), and the mechanism of action of potential radiation countermeasures. Our ultimate goal is to develop radiation countermeasures to protect military personnel, first responders and civilians from succumbing to ARS following radiation exposure whether it is accidental or as a result of deliberate attack. To achieve this goal we are currently investigating the mechanism of action of gamma-tocotrienol (GT3, an isomer of Vitamin E), Ex-RAD (a chlorobenzylsulphone derivative), toll-like receptor (TLR) ligands (CBLB502), and anti-ceramide antibody at the cellular level, by evaluating cell signaling pathways (cytokine expression, p53 pathway, TLR activation) including DNA damage and repair pathways.
In collaboration with corporate partners, my lab is developing several radiation countermeasures which are under advanced stages of development. CBLB502 and anti-cermide antibody appear to be promising. Ex-RAD has been shown to have both radioprotective and radiomitigative properties. Ex-RAD protects the hematopoietic system and is able to increase survival of irradiated mice by alleviating the severe radiation induced pancytopenia and restoring select bone marrow functions through the up-regulation of the PI3-kinase/AKT pathways and pathways involved with the DNA damage response and DNA repair. Ex-RAD studies have received significant funding from DMRDP (DoD) and BARDA (HHS).
My lab is also working to develop GT3, as a radiation countermeasure in collaboration with Prof. Martin Hauer-Jensen. It has shown great promise in rodent model, capable of mobilizing progenitors, and its radioprotective efficacy is mediated through G-CSF in murine model. Recently, we found that a single administration of GT3, without additional support (fluids, antibiotics, blood products, etc.), was just as effective as multiple administrations of G-CSF, the current gold standard of radiation countermeasures approved by US FDA, with full support. Based on the promising results of our pilot study using the large animal model, we have received funding from CDMRP (DoD) for the advanced development of GT3.
Additionally, we are working to develop a novel anti-ceramide antibody in collaboration with Prof. Richard Kolesnick of Sloan Kettering and Ceramide Theraprutics as a radiation countermeasure, capable of being administered prior to or after radiation exposure. Studies have indicated that this potential countermeasure inhibits ceramide-mediated endothelial apoptosis, which provides significant protection against radiation induced, potentially fatal, gastrointestinal syndrome. Additional studies have shown that a single chain variable fragment of the full length antibody molecule is effective in doses one tenth of the full length version. This project had been supported by DMRDP (DoD). Additional countermeasures being investigated are CBLB612, CBLB613, and myeloid progenitors in collaboration with various academic and corporate partners with support from various funding agencies such as BARDA, NIAID, JPC7, CDMRP, and DMRDP.
Representative publications, projects, and/or deployments
- G1B23687 Determination of radiation dose response for the AFRRI LINAC and subsequent non-clinical studies to evaluate potential medical countermeasures as mitigators of hematopoietic and/or low dose GI syndromes (H-ARS; GI-ARS) in an NHP model. Biomedical Advanced Research and Development Authority (BARDA), $8,535,865, September 15, 2015 – September 14, 2019
- G1B22927 Advanced development of gamma-tocotrienol as a radiation countermeasure. Congressionally Directed Medical Research Programs (CDMRP), $7,811,978, September 21, 2015 – September 20, 2019.
- G2B2HF Evaluation of radiation mitigators in nonhuman primates with supportive care. National Institute of Allergy and Infectious Diseases (NIAID), FY 2016 $406,581, FY 2017 $1,264,698, September 2015 – Sepetember 2017, Open ended, yearly renewal expected every year with additional budget.
- NAB22586 Advanced development of Ex-RAD as a radiomitigator. Defense Medical Research and Development Program (DMRDP), $ 1,198,000, April 2014 – September 2017
- G1B24024 Advanced Development of BIO 300 for Acute Radiation Syndrome and Delayed Effects of Acute Radiation Exposure, Congressionally Directed Medical Research Programs (CDMRP), $1,195,189, October 2016 – September 2019
- RAB24402 Biomarkers for radiation injury: Integrative omics study, AFRRI, $240,000, November 11, 2016 – September 30, 2019
- AFR-B2-4365 Development of Bio 301: An encapsulated nano-genistein therapy, Congressionally Directed Medical Research Programs (CDMRP), $712,295, POP to be negotiated
Bibliography
Biosketch Link:
- Singh VK, Seed TM: A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: Part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures. Int J Radiat Biol (in press: DOI: 10.1080/09553002.2017.1332438), 2017.
- Singh VK, Garcia M, Seed TM: A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: Part II. Countermeasures for limited indications, internalized radionuclides, emesis, late effects, and agents demonstrating efficacy in large animals with or without FDA IND status. Int J Radiat Biol (in press: DOI: 10.1080/09553002.2017.1338782), 2017.
- Singh VK, Hanlon BK, Santiago PT, Seed TM: A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: Part III. Countermeasures under early stages of development along with ‘standard of care’ medicinal and procedures not requiring regulatory approval for use. Int J Radiat Biol (in press: DOI: 10.1080/09553002.2017.1332440), 2017.
- Fendler W, Malachowska B, Meghani K, Konstantinopoulos PA, Guha C, Singh VK, Chowdhury C: Evolutionarily conserved serum microRNAs can predict radiation-induced fatality in non-human primates. Sci Transl Med 9:eaal2408, 2017
- Singh VK, Fatanmi OO, Wise SY, Newman VL, Romaine PLP, Seed TM: The potentiation of the radioprotective efficacy of two medical countermeasures, gamma-tocotrienol and amifostine, by a combination prophylactic modality. Radiat Prot Dosimetry 172:302-310, 2016.
- Singh VK, Kulkarni S, Fatanmi OO, Wise SY, Newman VL, Romaine PLP, Hendrickson H, Gulani J, Ghosh SP, Kumar KS, Hauer-Jensen M: Radioprotective efficacy of gamma-tocotrienol in nonhuman primates. Radiat Res 185:285-298, 2016.
- Krivokrysenko VI, Toshkov I, Gleiberman A, Krasnov P, Shyshynova I, Bespalov I, Maitra R, Narizhneva N, Singh VK, Whitnall MH, Purmal A, Shakhov A, Gudkov A, Feinstein E: TLR5 agonist Entolimod mitigates acute radiation syndrome in non-human primates. PLoS One 10:e0135388, 2015.
- Elliott TB, Bolduc DL, Ledney GD, Kiang JG, Fatanmi OO, Wise SY, Romaine PLP, Newman VL, Singh VK: Combined immunomodulator and antimicrobial therapy eliminates polymicrobial sepsis and modulates cytokine production in mice exposed to radiation and combined injury. Int J Radiat Biol 91:690-702, 2015.
- Dalgard CL, Jacobowitz DM, Singh VK, Saleem KS, Ursano RJ, Starr JM, Pollard HB: A novel analytical brain block tool to enable functional annotation of discriminatory transcript biomarkers among discrete regions of the fronto-limbic circuit in primate brain. Brain Res 1600:42-58, 2015.
- Singh VK, Wise SY, Fatanmi OO, Scott J, Romaine PLP, Newman VL, Verma A, Elliott TB, Seed TM: Progenitors mobilized by gamma-tocotrienol as an effective radiation countermeasure. PLoS ONE 9:e114078, 2014.
Andrew L Snow, Ph.D.
Name: Andrew L Snow, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Associate Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
human immunology, lymphocyte signaling & apoptosis, primary immune disorders
Email:
Office Phone:
(301) 295-3267
Education
B.S., Biology, Visual Arts, Duke University
Ph.D., Immunology, Stanford University School of Medicine
Postdoctoral Training, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH
Ph.D., Immunology, Stanford University School of Medicine
Postdoctoral Training, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH
Biography
RESEARCH INTERESTS
The major emphasis of my laboratory is to elucidate how aberrations in lymphocyte signaling contribute to deranged immune homeostasis in novel lymphoproliferative disorders and primary immunodeficiencies. Our research focuses on identifying novel molecular regulators of lymphocyte apoptosis and differentiation in humans, with the ultimate goal of informing new therapeutic approaches for controlling immune responses by manipulating cell death sensitivity.
ONGOING PROJECTS
1. Signal regulation and physiological relevance of specific T cell apoptosis pathways
The regulation and eventual contraction of activated T cells during an immune response is critical for maintaining equilibrium in the immune system and preventing unwanted damage to host tissues. Normally, specific apoptosis programs induced by T cell receptor (TCR) restimulation or cytokine withdrawal work to cull the majority of activated effector T cells, leaving a small pool of memory T cells behind to protect against subsequent infections (Fig 1). We now appreciate that genetic defects in lymphocyte apoptosis directly contribute to excess lymphoproliferation in humans. For example, T cells from patients with X-linked lymphoproliferative disease (XLP-1) display a profound defect in T cell receptor restimulation-induced cell death (RICD; also known as activation-induced cell death), a critical self-regulatory apoptosis program that constrains effector T cell expansion. Our lab has defined several biochemical mechanisms by which signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which is lost or mutated in XLP patients, facilitates RICD. Most recently, we led an international collaborative effort demonstrating that inhibition of diacylglycerol kinase alpha (DGKa), a modulatory enzyme with elevated activity in SAP-deficient T cells, presents a viable therapeutic approach for treating EBV-induced fulminant mononucleosis in XLP-1 patients, via restoration of RICD. Collectively, this work underscores the physiological relevance of RICD in preventing excessive T cell accumulation, severe immunopathology and mortality in XLP patients infected with EBV. We continue to investigate how RICD sensitivity is “tuned” via SAP-dependent signals.
We are also investigating novel links between metabolic programming and apoptosis sensitivity in human T cells. Our recent work indicates that while excessive anabolic metabolism (i.e. glycolysis) leaves effector T cells more susceptible to RICD, catabolic metabolism (i.e. autophagy) can protect T cells derived from distinct memory compartments from death induced by cytokine withdrawal. We have delineated specific molecular mechanisms responsible for these changes in cell death sensitivity, and continue to investigate how specific metabolic programs affect T cell viability. Our work illuminates how metabolic changes govern T cell survival, and may explain why certain memory T cells give rise to a larger, more robust effector response (via reduced cell death) that better protects the host when challenged with a pathogen or tumor.
2. Novel immunological disorders linked to mutations in CARD11
We discovered that gain-of-function (GOF) mutations in the CARD11 gene cause a rare congenital B cell lymphoproliferative disorder called B cell Expansion with NF-kB and T cell Anergy (BENTA) disease. My laboratory has taken a leading role in the genetic diagnosis and phenotypic characterization of an expanding cohort of BENTA patients (Fig 2). CARD11 encodes a scaffolding protein that links antigen receptor signaling to NF-kB activation in lymphocytes. Unlike the wild-type protein, CARD11 GOF mutants spontaneously oligomerize and drive constitutive activation of NF-kB, contributing to increased proliferation and enhanced survival of both immature and naïve patient B cells. Surprisingly, BENTA patients also exhibit hallmarks of immunodeficiency, including B cell differentiation defects, selective antibody deficiency, and opportunistic viral infections (e.g. molluscum contagiousum, chronic EBV) that reflect impaired T cell responses. Our latest findings pinpoint intrinsic molecular defects in plasma cell differentiation and antibody secretion in activated BENTA patient B cells, despite profound apoptosis resistance that likely explains excessive B cell expansion.
In collaboration with Dr. Joshua Milner (NIH) and others, we are also investigating loss-of-function (LOF) CARD11 mutations in atopic patients with severe eczema. We recently described 4 families with distinct, hypomorphic CARD11 mutations that dominantly interfere with WT CARD11 signaling, resulting in impaired NF-kB and mTORC1 signaling. Extensive structure-function studies of the CARD11 molecule continue in my lab, drawing from an expanding list of natural mutations in human patients. Using cell transfection systems, murine models and primary patient lymphocytes, my lab also continues to investigate how both GOF and LOF CARD11 mutations perturb signaling, differentiation and function of B and T cells.
The major emphasis of my laboratory is to elucidate how aberrations in lymphocyte signaling contribute to deranged immune homeostasis in novel lymphoproliferative disorders and primary immunodeficiencies. Our research focuses on identifying novel molecular regulators of lymphocyte apoptosis and differentiation in humans, with the ultimate goal of informing new therapeutic approaches for controlling immune responses by manipulating cell death sensitivity.
ONGOING PROJECTS
1. Signal regulation and physiological relevance of specific T cell apoptosis pathways
The regulation and eventual contraction of activated T cells during an immune response is critical for maintaining equilibrium in the immune system and preventing unwanted damage to host tissues. Normally, specific apoptosis programs induced by T cell receptor (TCR) restimulation or cytokine withdrawal work to cull the majority of activated effector T cells, leaving a small pool of memory T cells behind to protect against subsequent infections (Fig 1). We now appreciate that genetic defects in lymphocyte apoptosis directly contribute to excess lymphoproliferation in humans. For example, T cells from patients with X-linked lymphoproliferative disease (XLP-1) display a profound defect in T cell receptor restimulation-induced cell death (RICD; also known as activation-induced cell death), a critical self-regulatory apoptosis program that constrains effector T cell expansion. Our lab has defined several biochemical mechanisms by which signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which is lost or mutated in XLP patients, facilitates RICD. Most recently, we led an international collaborative effort demonstrating that inhibition of diacylglycerol kinase alpha (DGKa), a modulatory enzyme with elevated activity in SAP-deficient T cells, presents a viable therapeutic approach for treating EBV-induced fulminant mononucleosis in XLP-1 patients, via restoration of RICD. Collectively, this work underscores the physiological relevance of RICD in preventing excessive T cell accumulation, severe immunopathology and mortality in XLP patients infected with EBV. We continue to investigate how RICD sensitivity is “tuned” via SAP-dependent signals.
We are also investigating novel links between metabolic programming and apoptosis sensitivity in human T cells. Our recent work indicates that while excessive anabolic metabolism (i.e. glycolysis) leaves effector T cells more susceptible to RICD, catabolic metabolism (i.e. autophagy) can protect T cells derived from distinct memory compartments from death induced by cytokine withdrawal. We have delineated specific molecular mechanisms responsible for these changes in cell death sensitivity, and continue to investigate how specific metabolic programs affect T cell viability. Our work illuminates how metabolic changes govern T cell survival, and may explain why certain memory T cells give rise to a larger, more robust effector response (via reduced cell death) that better protects the host when challenged with a pathogen or tumor.
2. Novel immunological disorders linked to mutations in CARD11
We discovered that gain-of-function (GOF) mutations in the CARD11 gene cause a rare congenital B cell lymphoproliferative disorder called B cell Expansion with NF-kB and T cell Anergy (BENTA) disease. My laboratory has taken a leading role in the genetic diagnosis and phenotypic characterization of an expanding cohort of BENTA patients (Fig 2). CARD11 encodes a scaffolding protein that links antigen receptor signaling to NF-kB activation in lymphocytes. Unlike the wild-type protein, CARD11 GOF mutants spontaneously oligomerize and drive constitutive activation of NF-kB, contributing to increased proliferation and enhanced survival of both immature and naïve patient B cells. Surprisingly, BENTA patients also exhibit hallmarks of immunodeficiency, including B cell differentiation defects, selective antibody deficiency, and opportunistic viral infections (e.g. molluscum contagiousum, chronic EBV) that reflect impaired T cell responses. Our latest findings pinpoint intrinsic molecular defects in plasma cell differentiation and antibody secretion in activated BENTA patient B cells, despite profound apoptosis resistance that likely explains excessive B cell expansion.
In collaboration with Dr. Joshua Milner (NIH) and others, we are also investigating loss-of-function (LOF) CARD11 mutations in atopic patients with severe eczema. We recently described 4 families with distinct, hypomorphic CARD11 mutations that dominantly interfere with WT CARD11 signaling, resulting in impaired NF-kB and mTORC1 signaling. Extensive structure-function studies of the CARD11 molecule continue in my lab, drawing from an expanding list of natural mutations in human patients. Using cell transfection systems, murine models and primary patient lymphocytes, my lab also continues to investigate how both GOF and LOF CARD11 mutations perturb signaling, differentiation and function of B and T cells.
Bibliography
Biosketch Link:
- Voss K, Larsen SE, Snow AL. 2017. Metabolic reprogramming and apoptosis sensitivity: defining the contours of a T cell response. Cancer Letters 408:190-96.
- Arjunaraja S, Nosé BD, Sukumar G, Lott NM, Dalgard CL, Snow AL. 2017. Intrinsic Plasma Cell Differentiation Defects in BENTA Patient B Cells. Frontiers in Immunology 8: 913.
- Larsen SE, Voss K, Laing ED, Snow AL. 2017. Differential cytokine withdrawal-induced death sensitivity of effector T cells derived from distinct human CD8+ memory subsets. Cell Death Discovery 3:17031.
- Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ, Reynolds PR, Lyons JJ, Nelson CG, Ruffo E, Dorjbal B, Glauzy S, Stoddard J, Niemela J, Rosenzweig SD, McElwee JJ, DiMaggio T, Stone KD, Palma A, Oleastro M, Prieto E, Bernasconi A, Dubra G, Danielian S, Zaiat J, Marti M, Kim B, Cooper MA, Romberg N, Meffre E, Gelfand EW*, Snow AL*, Milner JD*. 2017. “Germline hypomorphic CARD11 mutations in severe atopic disease.” Nature Genetics 49:1192-1201.
- Larsen SE, Bilenkin A, Snow AL. 2017. Sensitivity to restimulation-induced cell death is linked to glycolytic metabolism in human T cells. Journal of Immunology 198: 147-55.
- Ruffo E, Malacarne V, Larsen SE, Das R, Patrussi L, Wulfing C, Biskup C, Schwartzberg PL, Baldari TC, Rubio I, Nichols KE*, Snow AL*, Baldanzi G*, Graziani A*. 2016. Inhibition of diacylglycerol kinase alpha restores TCR-induced diacylglycerol signaling and restimulation-induced cell death in XLP-1 T lymphocytes. Science Translational Medicine 8: 321ra7.
- Brohl AS, Stinson JR, Su HC, Badgett T, Jennings CD, Sukumar G, Sindiri S, Wang W, Moir S, Dalgard CL, Moscow JA, Khan J, Snow AL. 2015. Germline CARD11 mutation in a patient with severe congenital B cell lymphocytosis. Journal of Clinical Immunology, 35: 32-46. ePub Oct 2014.
- Katz G, Krummey SM, Larsen SE, Stinson JR, Snow AL. 2014. SAP facilitates recruitment and activation of LCK at NTB-A receptors during restimulation-induced cell death. Journal of Immunology 192: 4202-9.
- Snow AL, Xiao W, Chaigne-Delalande B, Pittaluga S, Stinson JR, Matthews HF, Lu W, Zheng L, Schmitz R, Jhavar S, Kuchen S, Lamborn IT, Jing H, Raffeld M, Su HC, Staudt LM, Lenardo MJ. 2012. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. Journal of Experimental Medicine 209: 2247-61.
- Snow AL, Marsh RA, Krummey SM, Roehrs P, Young LR, Zhang K, van Hoff J, Dhar D, Nichols KE, Filipovich AH, Su HC, Bleesing JJ, Lenardo MJ. 2009. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. Journal of Clinical Investigation 119: 2976-2989.
Aviva J Symes, Ph.D.
Name: Aviva J Symes, Ph.D.
USU Department of Primary Appointment:
Pharmacology & Molecular Therapeutics
Faculty Rank:
Full Professor
Location:
Uniformed Services University of the Health Sciences, Bethesda, MD
Research Interests:
Traumatic brain injury
Role of renin angiotensin system in the brain after injury
Email:
Office Phone:
(301) 295-3234
Education
B.Sc.(Hons). Biochemistry, University of Manchester, UK
Ph.D. Biochemistry/Molecular Biology, University College London, UK
Post-doctoral training: Massachusetts General Hospital/ Harvard Medical School, Boston.
Ph.D. Biochemistry/Molecular Biology, University College London, UK
Post-doctoral training: Massachusetts General Hospital/ Harvard Medical School, Boston.
Biography
RESEARCH INTERESTS:
My lab aims to understand the mechanisms through which the brain responds to traumatic injury and more specifically to delineate the pathways through which detrimental neuroinflammatory cascades can be altered to enhance recovery after injury. The initial lesion can produce significant tissue damage and breakdown of the blood brain barrier. These immediate effects lead to activation of many secondary cascades involving interplay between endogenous surviving neurons and glia, and infiltrating cells and molecules from the bloodstream. Injury therefore leads to acute neuroinflammatory cascades, and also to more chronic inflammatory effects. Indeed, activated microglia have been documented in postmortem brains many years after the initial insult. Our lab focuses on understanding the molecular signaling cascades that occur after injury in addition to testing potential therapeutics to enhance recovery from injury. We currently utilize several different rodent models of traumatic brain injury (TBI), with assays ranging from behavioral through molecular to understand the complex interactions that occur after injury, and to determine how manipulations may impact on functional recovery. We also utilize primary cell cultures to tease apart the molecular signaling pathways that contribute to inflammation after injury.
Angiotensin receptor blockers as potential therapeutics for TBI
Angiotensin receptor blockers (ARBs) are widely used FDA-approved anti-hypertension drugs with a favorable side effect profile that have been used as a mechanism for reducing the amount of TGF-β signaling in several different organ systems. In the CNS, ARBs have also been shown to be neuroprotective, anti-inflammatory and protective of the cerebral blood flow (CBF). The brain possesses its own renin angiotensin system, with many different components of the system expressed in the different cell types in the brain. However, in addition to acting as antagonists at the Angiotensin II receptor 1 (AT1R) some ARBs also possess potent PPARγ agonist activity that enhances their anti-inflammatory action. We have demonstrated that the ARB candesartan, lessens inflammation, reduces lesion volume, limits glial reactivity, increases neuronal survival and improves motor and cognitive recovery up to 28 days after injury. These beneficial effects are seen when low-dose candesartan is administered up to 6 hours after injury, a clinically acceptable therapeutic window. Our data suggest that both AT1 receptor antagonism and PPARγ agonism contribute to the efficacy of ARB treatment after TBI and it is this multimodal action by a single drug that makes it a strong candidate for TBI clinical trials. We are pursuing translational studies for candesartan for brain injury in addition to investigating the consequences of TBI on the endogenous renin-angiotensin system in the brain.
TGF-β signaling after injury
TGF-β is an injury induced cytokine that has complex roles in the central nervous system. After brain injury TGF-β can promote astrogliosis and enhance the deposition of molecules inhibitory to regeneration in the glial scar. Yet TGF-β is also neuroprotective indicating the sometimes conflicting roles of this cytokine. We have shown that after a penetrating brain injury mice that lack expression of the TGF-β signaling molecule Smad3, form a glial scar more quickly, with a smaller scar, than wild type mice. However, we also found that Smad3 null mice have more pronounced neuronal loss after injury. Thus, global interference with TGF-β signaling is not a desirable therapeutic option. Further, TGF-β is anti-inflammatory in some contexts – so chronic repression of TGF-β signaling pathways may enhance inflammation. In primary microglial cultures we have shown that inflammatory pathways downregulate TGF-β receptor expression, allowing for prolonged enhancement of the inflammatory activated state.
My lab aims to understand the mechanisms through which the brain responds to traumatic injury and more specifically to delineate the pathways through which detrimental neuroinflammatory cascades can be altered to enhance recovery after injury. The initial lesion can produce significant tissue damage and breakdown of the blood brain barrier. These immediate effects lead to activation of many secondary cascades involving interplay between endogenous surviving neurons and glia, and infiltrating cells and molecules from the bloodstream. Injury therefore leads to acute neuroinflammatory cascades, and also to more chronic inflammatory effects. Indeed, activated microglia have been documented in postmortem brains many years after the initial insult. Our lab focuses on understanding the molecular signaling cascades that occur after injury in addition to testing potential therapeutics to enhance recovery from injury. We currently utilize several different rodent models of traumatic brain injury (TBI), with assays ranging from behavioral through molecular to understand the complex interactions that occur after injury, and to determine how manipulations may impact on functional recovery. We also utilize primary cell cultures to tease apart the molecular signaling pathways that contribute to inflammation after injury.
Angiotensin receptor blockers as potential therapeutics for TBI
Angiotensin receptor blockers (ARBs) are widely used FDA-approved anti-hypertension drugs with a favorable side effect profile that have been used as a mechanism for reducing the amount of TGF-β signaling in several different organ systems. In the CNS, ARBs have also been shown to be neuroprotective, anti-inflammatory and protective of the cerebral blood flow (CBF). The brain possesses its own renin angiotensin system, with many different components of the system expressed in the different cell types in the brain. However, in addition to acting as antagonists at the Angiotensin II receptor 1 (AT1R) some ARBs also possess potent PPARγ agonist activity that enhances their anti-inflammatory action. We have demonstrated that the ARB candesartan, lessens inflammation, reduces lesion volume, limits glial reactivity, increases neuronal survival and improves motor and cognitive recovery up to 28 days after injury. These beneficial effects are seen when low-dose candesartan is administered up to 6 hours after injury, a clinically acceptable therapeutic window. Our data suggest that both AT1 receptor antagonism and PPARγ agonism contribute to the efficacy of ARB treatment after TBI and it is this multimodal action by a single drug that makes it a strong candidate for TBI clinical trials. We are pursuing translational studies for candesartan for brain injury in addition to investigating the consequences of TBI on the endogenous renin-angiotensin system in the brain.
TGF-β signaling after injury
TGF-β is an injury induced cytokine that has complex roles in the central nervous system. After brain injury TGF-β can promote astrogliosis and enhance the deposition of molecules inhibitory to regeneration in the glial scar. Yet TGF-β is also neuroprotective indicating the sometimes conflicting roles of this cytokine. We have shown that after a penetrating brain injury mice that lack expression of the TGF-β signaling molecule Smad3, form a glial scar more quickly, with a smaller scar, than wild type mice. However, we also found that Smad3 null mice have more pronounced neuronal loss after injury. Thus, global interference with TGF-β signaling is not a desirable therapeutic option. Further, TGF-β is anti-inflammatory in some contexts – so chronic repression of TGF-β signaling pathways may enhance inflammation. In primary microglial cultures we have shown that inflammatory pathways downregulate TGF-β receptor expression, allowing for prolonged enhancement of the inflammatory activated state.
Bibliography
Biosketch Link:
- Bone morphogenetic protein-2-mediated pain and inflammation in a rat model of posterolateral arthrodesis. Mitchell K, Shah JP, Dalgard CL, Tsytsikova LV, Tipton AC, Dmitriev AE, Symes AJ. BMC neuroscience. 2016; 17(1):80. PubMed [journal]PMID: 27905881 PMCID: PMC5134101
- Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Villapol S, Balarezo MG, Affram K, Saavedra JM, Symes AJ. Brain : a journal of neurology. 2015; 138(Pt 11):3299-315. PubMed [journal]PMID: 26115674 PMCID: PMC4731413
- Runx1 promotes proliferation and neuronal differentiation in adult mouse neurosphere cultures. Logan TT, Rusnak M, Symes AJ. Stem cell research. 2015; 15(3):554-564. PubMed [journal]PMID: 26473321
- Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan. Villapol S, Kryndushkin D, Balarezo MG, Campbell AM, Saavedra JM, Shewmaker FP, Symes AJ. The American journal of pathology. 2015; 185(10):2641-52. PubMed [journal]PMID: 26435412 PMCID: PMC4607758
- . Temporal patterns of cortical proliferation of glial cell populations after traumatic brain injury in mice. Susarla BT, Villapol S, Yi JH, Geller HM, Symes AJ. ASN neuro. 2014; 6(3):159-70. PubMed [journal]PMID: 24670035 PMCID: PMC4013687
- LPS antagonism of TGF-β signaling results in prolonged survival and activation of rat primary microglia. Mitchell K, Shah JP, Tsytsikova LV, Campbell AM, Affram K, Symes AJ. Journal of neurochemistry. 2014; 129(1):155-68. PubMed [journal]PMID: 24251648
- Temporal dynamics of cerebral blood flow, cortical damage, apoptosis, astrocyte-vasculature interaction and astrogliosis in the pericontusional region after traumatic brain injury. Villapol S, Byrnes KR, Symes AJ. Frontiers in neurology. 2014; 5:82. PubMed [journal]PMID: 24926283 PMCID: PMC4044679
- Smad3 deficiency increases cortical and hippocampal neuronal loss following traumatic brain injury. Villapol S, Wang Y, Adams M, Symes AJ. Experimental neurology. 2013; 250:353-65. PubMed [journal]PMID: 24120438
- TGF-β superfamily gene expression and induction of the Runx1 transcription factor in adult neurogenic regions after brain injury. Logan TT, Villapol S, Symes AJ. PloS one. 2013; 8(3):e59250. PubMed [journal]PMID: 23555640 PMCID: PMC3605457
- Candesartan, an angiotensin II AT₁-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice. Villapol S, Yaszemski AK, Logan TT, Sánchez-Lemus E, Saavedra JM, Symes AJ. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2012; 37(13):2817-29. PubMed [journal]PMID: 22892395 PMCID: PMC3499714
