Pharmacology

Iordanskiy Lab

Name: Iordanskiy Lab

Department of Primary Appointment: Pharmacology
Position: USU Staff
Title:

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SERGEY IORDANSKIY, PhDAssistant ProfessorAFRRI-46/4429B(301) 295-0580

Natallia Mikhalkevich, PhD

Research Associate

AFRRI-46/4429

(301) 295-3730

 

Singh Lab

Name: Singh Lab

Department of Primary Appointment: Pharmacology
Position: USU Staff
Title:

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Name                                                   Designation     Bldg/Rm     Telephone
Vijay K. Singh, PhD Professor       42/3118     (301) 295-2347
Mari NumanoiLieutenant, Navy   45/3321     (301) 295-9243
Oluseyi FatanmiResearch Biologist45/3117 (301) 295-3873
Stephen WiseResearch Supervisor (HJF)45/3120  (301) 319-4725
Amit Verma, PhDPost-doctoral fellow (NRC)46/4420  (301) 295-1843
Melissa Garcia Research Assistant (HJF)  45/3117   (301) 295-9263
Eric LeeResearch Assistant (HJF)  45/3118  (301) 295-9889
Briana Hanlon  Research Assistant (HJF)  45/3117   (301) 295-9233 
Paola SantiagoResearch Assistant (HJF)  45/3117  (301)295-0083
Anne Semon Research Assistant (HJF)   46/4420  (301) 295-1847
Madison SimasResearch Assistant (HJF)  46/4444  295-9289
Navjot Kaur  Intern (NREIP)   46/4444   319-0718 
Doris AkinneyeIntern (SEAP) 46/4444    319-0718 
 Sahana Epari Intern (HJF)       46/4434    295-0336 
 Tracy Le Intern (Infused Solutions)  46/4434    319-0718 

 

Rocio Cortez

Name: Rocio Cortez

Department of Primary Appointment: Pharmacology
Position: USU Staff
Title:

Email: juana.cortez@usuhs.edu (link sends e-mail)
Office Phone: (301) 295-3223

Irwin Lucki, PhD

Irwin Lucki

Name: Irwin Lucki, PhD

Department of Primary Appointment: Pharmacology
Position: Department Chair
Title: Professor & Chair

Research Interests:
Behavioral pharmacology; Mechanism of action of antidepressant and antianxiety medications; Stress neurobiology and psychiatric disorders

Email: irwin.lucki@usuhs.edu (link sends e-mail)
Office Phone: (301) 295-3248
Room: C2001

Links
PubMed Listing

Profile

Profile

  • B.A.: Psychology: University of Illinois at Chicago, 1972
  • M.A.: Psychology: University of Iowa, 1976
  • Ph.D.: Biopsychology: University of Iowa, 1979
  • Postdoctoral: Neuropsychopharmacology, University of Pennsylvania, 1981

Research Techniques

Behavioral pharmacology in rats and mice related to anxiety, depression and cognition; microdialysis measurement of extracellular concentrations of monoamines in conscious rats and mice; behavioral analysis of targeted genetic mutant mice; stereotaxic surgery; effects of brain lesions and neurotoxins on behavior; central drug administration; in vitro ligand binding; histology; analysis of hormones and neurotrophins by ELISA; and HPLC analysis of brain monoamines.

Behavioral Neuropharmacology of Depression and Anxiety

The research interests of the laboratory have focused on defining the role of specific neurotransmitters in the behavioral effects of drugs used in the treatment of psychiatric disorders. Animal models for depression and anxiety are used to evaluate the potential efficacy of different neurotransmitter and peptide receptors for clinical therapeutic effects, to identify brain regions associated with behavioral responses to drugs, and to construct and evaluate pharmacological models for improving the efficacy of psychiatric medications. The participation of genetic and pharmacological modifications of neural circuits in depression, anxiety and neuroendocrine regulation associated with behavioral stress has specifically been investigated. Microdialysis procedures are used to measure the release of neurotransmitters in discrete regions of awake freely-moving rats or mice.  These studies provide information on the regulation of the release of neurotransmitters in different brain regions, determine environmental and behavioral conditions that alter the release of neurotransmitters, and measure the effects of drugs during behavioral performance.  Finally, studies of different inbred mouse strains or knockout mice are used to examine genetic factors associated with complex behaviors and for identifying mechanisms underlying the behavioral effects of psychotherapeutic medications.

Most recently, our research program has focused on establishing neural mechanisms through animal behavior models for the clinical use of rapid-acting antidepressants for treatment-resistant forms of depression and anxiety.   Studies have focused on glutamatergic compounds, such as ketamine, and diverse opioid compounds, such as buprenorphine, nalmefene and selective kappa opioid receptor antagonists.  Behavioral studies have shown long-lasting antidepressant-like effects for these compounds under conditions where established antidepressants are ineffective.  Pharmacological studies are examining the mechanisms underlying the unusually long duration of their behavioral effects. 

KEY WORDS:   Antidepressants; tranquilizers; stress; serotonin; opioid receptors; microdialysis; knockouts; behavior

Selected Publications

Balu D.T, Carlson G.C., Talbot K., Kazi H., Hill-Smith T.E., Easton R.M., Birnbaum M. and Lucki I.  Akt1 deficiency in schizophrenia and impairment of hippocampal plasticity and function. Hippocampus, 22:230-40, 2012.

Balu D.T., Hodes G.E., Anderson B.T., and Lucki I. Enhanced sensitivity of the MRL/MpJ mouse to the neuroplastic and behavioral effects of chronic antidepressant treatments. Neuropsychopharmacology, 34: 1764-1773, 2009.

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, 33: 2117-2130, 2008.

Browne C.A. and Lucki I.  Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants.  Frontiers in Pharmacology 4:161, 2013.

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, 35: 752-763, 2010.

Hodes G.E., Hill-Smith T.E., Suckow R.F., Cooper T.B. and Lucki I. Sex-specific effects of chronic fluoxetine treatment on neuroplasticity and pharmacokinetics in mice.  J Pharmacol Exp Ther, 332:266-273, 2010. PMC2802485

Falcon, E., Maier, K., Robinson, S.A. and Lucki I. Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice.  Psychopharmacology, 232:907-915, 2015.  PMC4326609

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, in press.

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, 40:2517-2525, 2015.  PMC4569959

Recent Postdoctoral Fellows:  Caroline A. Browne, Ph.D.; Edgardo Falcon, Ph.D.

Graduate Students:  Shivon A. Robinson

Lab Alumni:

Postdocs:  Bethany R. Brookshire, Georgia E. Hodes, Anita J. Bechtholt, Candace E. Hoffmann, Brian A. Hoshaw, Michelle E. Jones-London, Arthur J. Mayorga, John F. Cryan, Ashutosh Dalvi, Jean-Philippe Reneric, M.D., Peter Rittenhouse, Carol Lopez-Rubalcava, Ashish Singh, William D. Essman, Angela Allen, Randy L. Smith, Grace Rowan, Scott Wieland.

Predocs: Nancy Ho, Greg V. Carr, Darrick T. Balu, Owen Howard, James J. Crowley, Olivia F. O’Leary, Deborah A. Knobelman, Michelle L. Price, Jennifer M. Chou, Patricia M. Furlan, Christine M. Andrews, Gregg Stanwood, Lynn G. Kirby, Michael J. Detke, M.D., Ph.D., Jed Shumsky, Deborah S. Kreiss.

Robert L. Kortum, M.D., Ph.D.

Robert Kortum

Name: Robert L. Kortum, M.D., Ph.D.

Department of Primary Appointment: Pharmacology
Position: USU Faculty
Title: Assistant Professor

Affiliated Departments: Molecular & Cell Biology,

Research Interests:
Signal Transduction, Cancer

Email: robert.kortum@usuhs.edu (link sends e-mail)
Office Phone: (301) 295-3249
Fax Number: (301) 295-3220
Room: C2027

Links
Department Website

Profile

  • B.S., Chemistry and Mathematics, University of Nebraska-Lincoln
  • Ph.D., Pathology and Microbiology, University of Nebraska Medical Center
  • M.D., University of Nebraska Medical Center
  • Postdoctoral Training, National Institutes of Health

Oncogenic RTK/Ras signalingTargeting RTK/Ras signaling in cancer

 

Oncogenic mutations in RTK/Ras signaling pathways account for 30-50% of tumors. For cancers driven by mutated or hyperactivated RTKs, targeted therapeutics have shown enormous potential, however, resistant cells often emerge that continue to rely on RTK signaling to drive their oncogenic phenotype. Similarly, for cancers driven by the Ras effector B-Raf, resistance to kinase inhibit ors often involves hyperactivation of RTK signaling.  It is therefore incumbent to find alternative therapeutic targets within the RTK/Ras pathway that when inactivated will limit oncogenesis.

 

 

Simultaneous targeting of multiple signaling proteins within the same pathway has the potential to overwhelm a cancer cell’s ability to mutate and become resistant to therapy. A major goal of our laboratory is to elucidate those signaling proteins downstream of RTKs that can be targeted either alone or in combination with current therapeutics to treat cancer.

 

Schematic depicting oligomerization of RTKs by Grb2—Sos—Grb2 complexesExamining novel Sos-dependent functions in RTK/Ras signaling

 

The RasGEFs (Guanine Exchange Factors) Sos1 and Sos2 (Son of Sevenless 1 and 2) are central to signal transduction from receptor tyrosine kinases (RTKs) to the small G protein Ras, and recruitment of the RasGEF Sos1 by the adaptor Grb2 to receptor signaling complexes is an essential early step in normal Ras activation. In T cells, Sos1 and Grb2 show multipoint binding that nucleate higher-order protein complexes at the cell surface necessary to drive cell fate decisions (Kortum, Sci. Signaling, 2013).  We are currently examining whether similar mechanisms are important to both normal and oncogenic RTK/Ras signaling

Symes Lab

Name: Symes Lab

Department of Primary Appointment: Pharmacology
Position: USU Faculty
Title:

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AVIVA J. SYMES, PhDProfessorC2126(301) 295-3234
Milan Rusnak DVM, PhDresearch scientistC2045(301) 295-3235
Nagesh Shanbhag, MD, PhDpost-doctoral fellowC2045(301) 295-3235
Peter AttilioPhD studentC2045(301) 295-3235
Zachary JanatpourMD PhD studentC2045(301) 295-3235
Alexandra Yaszemski
PhD studentC2045(301) 295-3235 

 

Snow Lab

Name: Snow Lab

Department of Primary Appointment: Pharmacology
Position: National Faculty
Title:

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Snow, Andrew, Ph.D.Assistant Professor (USU)C2013295-3267
Swadhinya Arjunaraja, Ph.D.Postdoctoral Fellow (HJF)C2033295-9742
Batsukh Dorjbal, Ph.D.Postdoctoral Fellow (HJF)C2033295-9742
Camille LakeGraduate Student (EID)C2033295-9742
Kelsey VossGraduate Student (EID)C2037295-9744
    
ONGOING PROJECTS

1. Signal regulation and physiological relevance of specific T cell apoptosis pathways

Snow fig 1The 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

Snow fig 2We 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.

Shewmaker Lab

Name: Shewmaker Lab

Department of Primary Appointment: Pharmacology
Position: National Faculty
Title:

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Shewmaker, Frank, Ph.D.Assistant Professor (USU)C2125(301) 295-3527

Rhoads, Shannon

Yee, Debra

Lab Manager

Technician

C2040

C2040

(301) 295-3229

(301) 295-3229

 

Nugent Lab

Name: Nugent Lab

Department of Primary Appointment: Pharmacology
Position: USU Staff
Title:

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Nugent, FereshtehAssociate Professor (USU)C2129301-295-3243
Kassis, HaifaPostdoctoral Research Associate (HJF)C2024301-295-3908
Langlois, LudovicPostdoctoral Fellow (HJF)C2018301-295-3221
Authement, MichaelGraduate Student (STU)C2018301-295-3221
Shepard. RyanGraduate Student (STU)C2024301-295-3908

Kortum Lab

Name: Kortum Lab

Department of Primary Appointment: Pharmacology
Position:
Title:

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Kortum, Robert, Ph.D.Assistant Professor (USU)C2027295-3249

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