PAT Faculty

Profile

Education

• Hahnemann School of Medicine, Drexel University. Ph.D., 1980

Current Research Interests:

My research focuses on the contributions of the transforming growth factors, oncogenes and tumor suppressor genes to the malignant transformation of cells and the loss of differentiated cell functions. Ongoing projects include the study of Rsu-1, the Ras suppressor molecule, the mechanisms by which it regulates tumor cell adhesion and the role of adhesion in the response of tumor cells to chemotherapeutic agents. The other area of research in my lab focuses on the control of mammary epithelial cell differentiation during development.

Rsu1 was identified based on its property of specifically suppressing Ras transformation in both fibroblasts and epithelial cells. The defining elements of the Rsu-1 protein are a series of amphipathic leucine-based repeats, referred to as leucine-rich repeats or LRR which bind to the adaptor protein PINCH1 (Dougherty et al. 2005, 2008). A complex of parvin-integrin linked kinase (ILK)-PINCH1-Rsu-1 participates in cell adhesion by linking beta subunits of integrin to the actin cytoskeleton. The knockdown of any of these proteins in cell culture results in loss of cell adhesion.

Ectopic Rsu-1 expression prevents both oncogenic growth of specific human glial and breast tumor cell lines and tumor formation in a nude mouse model. Screening human tumors for RSU-1 loss and mutation revealed that glial tumors frequently expressed an altered spliced product of the RSU-1 gene. This RNA is missing a single exon and encodes an Rsu-1 protein lacking the COOH terminus (Chunduru et al. 2002). Alternative splicing of Rsu-1 in human tumor cell lines is dependent on activation of Ras pathway (Dougherty et al., 2008) and studies examining the regulatory function of the alternatively spliced RNA in breast and glial tumors are ongoing in the lab.

The impact of tumor cell adhesion on the response of solid tumors to chemotherapy is an application of our work on the parvin-ILK-PINCH1-Rsu-1 complex and we are pursuing this project in collaboration with Dr. Peter D’Arpa, an expert on topoisomerase function.

The regulation of mammary epithelial cell differentiation.

Epidemiological evidence indicates that early pregnancy and lactogenic differentiation can reduce the risk of both pre- and post-menopausal breast carcinoma. Hence, a complete understanding of the regulation of mammary differentiation is important in elucidating the mechanisms leading to breast carcinogenesis. Global expression profiling of mammary epithelial cells undergoing lactogenic differentiation identified the matricellular protein connective tissue growth factor (CTGF/CCN2) as highly up regulated during lactogenic differentiation and that CTGF/CCN2 binding to ?1 integrin is required for differentiation (Wang et al. 2007 and Morrison et al. 2010). The potential application of this work to human breast cancer is significant because the molecular signature of genes transcriptionally activated during differentiation includes a number of transcripts that are found at high levels in breast tumors that metastasize to bone, a site of CTGF/CCN2 expression. Hence, the results of our analysis of differentiating mammary epithelial cells may help define elements of transcriptional control that are important for tumor progression in this tissue.

Selected Publications

Chunduru S, Kawami H, Gullick R, Dougherty G and Cutler ML. Identification of an alternatively spliced form of the Ras Suppressor RSU-1 in human gliomas. Journal of Neuro-Oncology 60: 201-211. 2002.

Cerritto MG, Galbaugh T, Chopp T, Wang W, Salomon D and Cutler ML. Dominant negative Ras enhances lactogenic hormone-induced differentiation by blocking activation of the Raf-Mek-Erk signal transduction pathway. Journal of Cellular Physiology, 201:244-258, 2004.

Dougherty G, Chopp T, Qi SM and Cutler ML. The Ras suppressor Rsu-1 binds to the LIM5 domain of the adaptor protein PINCH1 and participates in adhesion-related functions. Experimental Cell Research, 306: 168-179, 2005.

Galbaugh T, Cerrito MG, Jose C, Cutler ML. EGF-induced activation of Akt results in mTOR-dependent p70S6 kinase phosphorylation and inhibition of HC11 cell lactogenic differentiation. BMC Cell Biology, 7:34, 2006.

Gao CF, Furge K, Koeman J, Dykema K, Su Y, Cutler ML, Werts A, Haak, P, and Vande Woude GF. Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations. Proc. Nat. Acad. Sci. 104:8995-9000, 2007.

Dougherty G, Jose C, Gimona M and Cutler ML. The Rsu-1- PINCH1-ILK complex is regulated by Ras activation in tumor cells. European Journal of Cell Biology, 87:721-734, 2008.

Wang W, Jose C, Kenney N, Morrison B and Cutler ML. Global expression profiling reveals transcriptional regulation of CTGF/CCN2 during lactogenic differentiation. Journal of Cell Communication and Signaling, 3:43-55. 2009.

Morrison B, Kenney N, Jose C, and Cutler ML. Connective Tissue Growth Factor/CCN2 enhances lactogenic differentiation of mammary epithelial cells via integrin-mediated cell adhesion. BMC Cell Biology 11:35. 2010.

Morrison B and ML Cutler. The contribution of adhesion signaling to lactogenesis. Journal of Cell Communication and Signaling. 4:131-139. 2010.

Morrison B and ML Cutler. The Contribution of CTGF/CCN2 and adhesion signaling to lactogenesis. In Dietary and Nutritional Aspects of Human Breast Milk. Academic Publishers, Wageningen, the Netherlands. 2012.

Profile

Education

Queen Mary, University of London, UK, Ph.D., 1994

Current Research Interests:

Bacteria belonging to the family Deinococcaceae are some of the most radiation-resistant organisms yet discovered. Deinococcus radiodurans was first reported in 1956 by Andy Anderson and coworkers of the Oregon Agricultural Experimental Station, Corvalis, Oregon. The genes and cellular pathways underlying the survival strategies of D. radiodurans have been under investigation ever since, and its resistance characteristics are being exploited in the development of bioremediation processes for cleanup of highly radioactive US Department of Energy waste sites. One original goal of radiobiology was to explain why cells are so sensitive to ionizing radiation (IR). Early studies in bacteria incriminated DNA as the principal radiosensitive target, an assertion that remains central to modern radiation toxicity models. More recently, the emphasis has shifted to understanding why bacteria such as D. radiodurans are extremely resistant to IR. Unfortunately, as key features of DNA-centric hypotheses of extreme resistance have grown weaker, the study of alternative cellular targets has lagged far behind, mostly because of their relative biological complexity. Recent studies have shown that extreme levels of bacterial IR resistance correlate with high intracellular Mn(II) concentrations, and resistant and sensitive bacteria are equally susceptible to IR-induced DNA damage. Our most recent work has established a mechanistic link between Mn(II) and protection of proteins from radiation damage. In contrast to resistant bacteria, naturally sensitive bacteria are highly susceptible to IR-induced protein oxidation. We have proposed that sensitive bacteria sustain lethal levels of protein damage at radiation doses that elicit relatively little DNA damage, and that extreme resistance in bacteria is dependent on protein protection.

Representative Publications: 1994-2006

H. Brim, J. P. Osborne, H. M. Kostandarithes, J. K. Fredrickson, L. P. Wackett and MICHAEL J. DALY (2006) Deinococcus radiodurans engineered for complete toluene degradation facilitates Cr(VI) reduction. Microbiology, Aug;152(Pt 8):2469-77.

X. Qiu, MICHAEL J. DALY, A. Vasilenko, M. V. Omelchenko, L. Wu, J. Zhou, G. W. Sundin and J. M. Tiedje (2006) Transcriptome analysis applied to survival of Shewanella oneidensis MR-1 exposed to ionizing radiation. J. Bacteriol., 188, 1199-1204.

J. W. Szostak, R. E. Blake, MICHAEL J. DALY, D. H. Grinspoon, A. D. Keefe and G. J. Olsen (2006) Assessment of Planetary Protection Requirements for Venus Missions. National Academy Press, Commission on Physical Sciences, Mathematics, and Applications.

J. Qin, L. Song, Hassan Brim, MICHAEL J. DALY and A. O. Summers (2006) Sequestration and protection by the MerR metal binding domain (MBD). Microbiology, 152, 709-719.

MICHAEL J. DALY (2006) Modulating radiation resistance: Insights based on defenses against reactive oxygen species (ROS) in the radioresistant bacterium Deinococcus radiodurans. Clin. Lab. Med. 26, issue 2, In Press.

M. V. Omelchenko, Y. I. Wolf, E. K. Gaidamakova, V. Y. Matrosova, A. Vasilenko, MICHAEL J. DALY, E. V. Koonin and K. S. Makarova (2005) Comparative genomics of Thermus thermophilus HB27 and Deinococcus radiodurans R1: Divergent paths of adaptation to thermophily and radiation resistance. BMC Evolutionary Biology, 5, 57-79.

D. Ghosal, M. V. Omelchenko, E. K. Gaidamakova, V. Y. Matrosova, A. Vasilenko, A. Venkateswaran, H. M. Kostandarithes, H. Brim, K. S. Makarova, L. P. Wackett, J. K. Fredrickson and MICHAEL J. DALY (2005) How radiation kills cells: Survival of Deinococcus radiodurans and Shewanella oneidensis under oxidative stress. FEMS Microbiology Reviews 29, 361-375.

J. Szostak, J. C. Wheeler, S. A. Benner, J. Berry, R. Blake, W. Calvin, MICHAEL J. DALY, K. H. Freeman, J. P. Gogarten, J. F. Kasting, A. Keefe, M. Keller, S. Pizzarello, J. Siefert, R. Summons, N. Woolf and L. M. Ziurys (2005) The astrophysical context of life. The National Academies Press, National Academy of Sciences, Washington, D.C,

MICHAEL J. DALY, E. K. Gaidamakova, V. Y. Matrosova, A. Vasilenko, M. Zhai, A. Venkateswaran, M. Hess, M. V. Omelchenko, H. M. Kostandarithes, K. S. Makarova, L. P. Wackett, J. K. Fredrickson and D. Ghosal (2004) Accumulation of Mn(II) in Deinococcus radiodurans facilitates gamma-radiation resistance. Science 306, 925-1084.

J. K. Fredrickson, J. M. Zachara, D. L. Balkwill, D. Kennedy, S. W. Li, H. M. Kostandarithes, MICHAEL J. DALY, M. F. Romine and F. J. Brockman (2004) Geomicrobiology of high level nuclear waste contaminated vadose sediments at the Hanford Site, Washington state. Appl. Environ. Microbiol. 70, 4230-4241.

M. Sandigursky, S. Sandigursky, P. Sonati, MICHAEL J. DALY and W. A. Franklin (2004) Multiple uracil-DNA glycosylase activities in D. radiodurans. DNA Repair, 3, 163-169.

J. R. Battista, M. M. Cox, MICHAEL J. DALY, I. Narumi, M. Radman and S. Sommer (2003) The structure of Deinococcus radiodurans. Science, 302, 567-568.

H. Brim, A. Venkateswaran, H. M. Kostandarithes, J. K. Fredrickson and MICHAEL J. DALY (2003) Genetic development of D. geothermalis for bioremediation of high temperature radioactive waste environments. Appl. Environ. Microbiol., 69, 4575-4582.

Y. Liu, J. Zhou, A. Beliaev, J. Stair, L. Wu, D.K. Thompson, D. Xu, A. Venkateswaran, M. Omelchenko, M. Zhai, E. K. Gaidamakova, K. S. Makarova, E. Koonin and MICHAEL J. DALY (2003) Transcriptome dynamics of Deinococcus radiodurans recovering from ionizing radiation. Proc. Natl. Acad. Sci. USA, 100, 4191-4196.

M. S. Lipton, L. Pasa-Tolic, G. A. Anderson, D. J. Anderson, D. Auberry, J. R. Battista, MICHAEL J. DALY, J. K. Fredrickson, K. K. Hixson, H. Kostandarithes, T. Conrads, C. Masselon, M. Markille, R. J. Moore, M. F. Romine, Y. Shen, N. Tolic, H. R. Udseth, T. D.Veenstra, A. Venkateswaran , K. K Wong, R. Zhao and R. D. Smith (2002) Global analysis of the Deinococcus radiodurans R1 proteome using accurate mass tags. Proc. Natl. Acad. Sci. USA. 99, 11049-11054.

J-I Kim, A. K. Sharma, S. N. Abbot, E. A Wood, D. Dwyer, A. Jambura, K. W. Minton, R B. Inman, MICHAEL J. DALY and M. M. Cox (2002) RecA protein from the extremely radioresistant bacterium Deinococcus radiodurans: Expression, purification, and characterization.

MICHAEL J. DALY (2002) The Quarantine and certification of martian samples: Appendix A: Deinococcus radiodurans as an analogue to extremophile organisms that may have survived on Mars. National Academy Press, Commission on Physical Sciences, Mathematics, and Applications, pp. 67-69

K. S. Makarova, L. Aravind, Y. I. Wolf, R. L.Tatusov, K. Minton, E. V. Koonin and MICHAEL J. DALY (2001) The genome of the extremely radiation resistant bacterium Deinococcus radiodurans viewed from the perspective of comparative genomics. Microbiology and Molecular Biology Reviews 65, 44-79.

MICHAEL J. DALY (2001) The emerging impact of genomics on the development of biological weapons: Threats and benefits posed by engineered extremophiles. Clinics in Laboratory Medicine 21, 619-629.

J. Nolling, G. Breton, M. V. Omelchenko, K. S. Makarova, Q. Zeng, R., Gibson, H. M. Lee, J. Dubois., D. Qiu, J. Hitti, Y. I. Wolf, R. L., Tatusov, F. Sabathe, L. Doucette-Stamm, R. L. Tatusov, P. Soucaille, MICHAEL J. DALY, G. N. Bennett, E. V. Koonin and D. R. Smith (2001) Genome sequence and comparative analysis of the solvent-producing bacterium Clostridium acetobutylicum. J. Bacteriol. 183, 4823-4838.

A. F. Cheng, B. C. Clark, MICHAEL J. DALY, E. I. Friedman, B. M. Jakosky, R. Y Morita, A.-L. Reysenbach, D. A. Stahl and L. W. Esposito (2001) Planetary Protection for Europa, Space Studies Board, National Research Council, National Academy of Sciences, Washington, D.C.

MICHAEL J. DALY (2000) Engineering radiation-resistant bacteria for environmental biotechnology. Current Opinion in Biotechnology 11, 280-285.

H. Brim, S. McFarlan, L. Wackett, K. W. Minton, M. Zhai, J. Fredrickson and MICHAEL J. DALY (2000) Engineering Deinococcus radiodurans for metal remediation in radioactive mixed waste environments. Nature Biotechnology 18, 85-90.

J. K. Fredrickson, H. M. Kostandarithes, A. W. Li, A. E. Pyle and MICHAEL J. DALY (2000) Reduction of Fe(III), Cr(VI), U(VI), and Tc(VII) by Deinococcus radiodurans. Appl. Environ. Microbiol. 66, 2006-2011.

A.Venkateswaran, S. C. McFarlan, D. Ghosal, K. W. Minton, A. Vasilenko, K. Makarova, L. P. Wackett and MICHAEL J. DALY (2000) Physiologic determinants of radiation resistance in Deinococcus radiodurans. Appl. Environ. Mircobiol. 66, 2620-2626.

K. S. Makarova, L. Aravind, MICHAEL J. DALY and E. V. Koonin (2000) Specific expansion of protein families in the radioresistant bacterium Deinococcus radiodurans. Genetica 108, 25-34.

O. White, J. A. Eisen, J. F. Heidelberg, E. K. Hickey, J.D. Peterson, R. J. Dodson, C. Zalewski, K. S. Makarova, L. Aravind, MICHAEL J. DALY, K. W. Minton, R. D. Fleischmann, K. A. Ketchum, K. E. Nelson, S. Salzberg, H. O. Smith, J. C. Venter, C. M. Fraser et al., (1999) Sequencing and functional analysis of the Deinococcus radiodurans genome. Science 286, 1571-1577.

J. Lin, R. Qi, C. Aston, J. Jing, T. S. Anantharaman, B. Mishra, O. White, K. W. Minton, MICHAEL J. DALY, J. C. Venter and D. C. Schwarzt (1999) Whole genome shotgun optical mapping of Deinococcus radiodurans using genomic DNA molecules. Science 285, 1558-1561.

R. C. Richmond, R Sridhar and MICHAEL J. DALY (1999) Physicochemical survival pattern for the radiophile Deinococcus radiodurans: A polyextremophile model for life on Mars. SPIE, 3755, 210-222.

K. S. Makarova, Y. I. Wolf, K. W. Minton, O. White and MICHAEL J. DALY (1999) Short repeats and insertional elements in Deinococcus radiodurans and comparison to other bacterial species. Res. Microbiol. 150, 711-724.

C. Lange, L. P. Wackett, K. W. Minton and MICHAEL J. DALY (1998) Engineering a recombinant Deinococcus radiodurans for organopollutant degradation in radioactive mixed waste environments. Nature Biotechnology 16, 929-933.

MICHAEL J. DALY and K. W. Minton (1997) Recombination between a resident plasmid and the chromosome following irradiation of the radioresistant bacterium Deinococcus radiodurans. Gene 187, 225-229.

J. D. Carroll, MICHAEL J. DALY and K. W. Minton (1996) Expression of recA in Deinococcus radiodurans. J. Bacteriol. 178, 130-135.

MICHAEL J. DALY and K. W. Minton (1996) An alternative pathway for recombination of chromosomal fragments precedes recA-dependent recombination in the radioresistant bacterium Deinococcus radiodurans. J. Bacteriol. 178, 4461-4471.

MICHAEL J. DALY and K. W. Minton (1995) Resistance to radiation. Science 270, 1318.

K. W. Minton and MICHAEL J. DALY (1995) A model for repair of radiation induced DNA DSBs in the extreme radiophile Deinococcus radiodurans. Bioessays 17, 457-464.

MICHAEL J. DALY and K. W. Minton (1995) Interchromosomal recombination in the extremely radioresistant bacterium Deinococcus radiodurans. J. Bacteriol. 177, 5495-5505.

MICHAEL J. DALY, L. Ouyang, P. Fuchs and K. W. Minton (1994) In vivo damage and recA-dependent repair of plasmid and chromosomal DNA in the radioresistant bacterium Deinococcus radiodurans. J. Bacteriol. 176, 3508-3517.

MICHAEL J. DALY, L. Ouyang and K. W. Minton (1994) Interplasmidic recombination following irradiaition of the radioresistant bacterium Deinococcus radiodurans. J. Bacteriol. 176, 7506-7515.

Current Research Interests:

Vector- and tick-borne diseases and pathogenic agents

• Studies of the basic biology to clinical aspects of vector-borne infections of humans and animals.
• Focus on tick-borne infections, especially those caused by obligate intracellular bacteria in the order Rickettsiales.

Anaplasma phagocytophilum AnkA and epigenetic eukaryotic gene regulation

• Bacterial cellular and molecular mechanisms of adherence and entry
• Mechanisms by which the bacteria manipulate host cell transcriptional programs
• AnkA, a protein injected into host cells that alters chromatin and nuclear structure and influences eukaryotic gene transcription
• Genomics

Bacterial infections and immunopathology mediated by NKT and cytotoxic T cells

• A. phagocytophilum immunopathology related to NKT, NK, and CD8 T cells immune responses.
• Stat1 signaling and its role in immunopathology with A. phagocytophilum infection.

Bacterial coinfections and their synergistic mechanisms in pathology

• Interactions between Lyme disease and HGA clinical presentation and severity.
• The role of matrix metalloproteases and the fibrinolytic system in transendothelial cell dissemination

Vascular permeability, pathogen entry, invasion and dissemination

• Transmigration of endothelial cell barriers by Borrelia, Rickettsia, Ehrlichia and other pathogens
• The role of intracellular calcium concentrations, divalent cation chelators, phospholipase C inhibitors and signaling through G protein coupled receptors

Clinical investigation of febrile disease etiology in under-resourced regions

• Specific microbial etiologies of febrile diseases in regions where resources are limited.
• Objective diagnostic approaches, misdiagnosis, inappropriate treatment and the consequent negative outcomes.
• How much fever in such regions is the result of undiagnosed rickettsial disease?
• Clinical studies and trials to test new diagnostic tests, new therapies and vaccines.
• High-throughput molecular diagnostic methods in Malaysia, Sri Lanka, and Nicaragua.

Selected Publications since 2014

1.      Sinclair SHG, Garcia-Garcia JC, Dumler JS. Bioinformatic and mass spectrometry identification of Anaplasma phagocytophilum proteins translocated into host cell nuclei. Front Microbiol 2015 6:55. PMC4319465.

2.      Bakken JS, Dumler JS. Human Granulocytic Anaplasmosis. Infect Dis Clin North Am. 2015; 29:341-355. PMC4441757

3.      Li H, Zheng YC, Ma L, Jia N, Jiang BG, Jiang RR, Huo QB, Wang YW, Liu HB, Chu YL, Song YD, Yao NN, Sun T, Zeng FY, Dumler JS, Jiang JF, Cao WC. Human infection with a novel tick-borne Anaplasma species in China: a surveillance study. Lancet Infect Dis 2015 Mar 27. pii: S1473-3099(15)70051-4. PMID: 25833289

4.      Chikeka I, Dumler JS. Neglected Bacterial Zoonoses. Themed Review in Clin Microbiol Infect Dis 2015; 21:404-415. PMC4466158

5.      Rennoll-Bankert KE, Garcia-Garcia JC, Sinclair SH, Dumler JS. Chromatin bound bacterial effector AnkA recruits HDAC1 and modifies host gene expression. Cell Microbiol 2015; 17:1640-52. PMID: 25996657.

6.      Sinclair SHG, Yegnasubramanian S, Dumler JS. Global DNA methylation changes and differential gene expression in Anaplasma phagocytophilum-infected human neutrophils. Clin Epigenetics 2015; 7:77. PMC4518890

7.      André MR, Dumler JS, Herrera HM, Gonçalves LR, de Sousa KCM, Scorpio DG, Alexandre de Santis ACG, Domingos IH, Carvalho de Macedo G, Zacarias Machado R. Assessment of a quantitative 5’ nuclease real-time polymerase chain reaction using the nicotinamide adenine dinucleotide dehydrogenase gamma subunit (nuoG) for Bartonella species in domiciled and stray cats in Brazil. J Fel Med Surg 2015 [in press].

8.      Dittrich S, Phuklia W, Turner GDH, Rattanavong S, Dumler JS, Paris DH, Newton PN. Sennetsu as a neglected fish-borne cause of fever in South-East Asia. PLoS Negl Trop Dis. 2015; 9:e0003908. doi:10.1371/journal.pntd.0003908. PMC4497638.

9.      Huang X, Zhang X, Wang F, Wei H, Ma H, Sui M, Lu J, Wang H, Dumler JS, Sheng G, Xu B. Clinical efficacy of therapy with recombinant human interferon α1b in hand, foot, and mouth disease with Enterovirus 71 infection. PLoS One. 2016; 11:e0148907. PMC4755579.

10.  Wang X, Shaw DK, Sakhon OS, Snyder GA, Sundberg EJ, Santambrogio L, Sutterwala FS, Dumler JS, Shirey KA, Perkins DJ, Richard K, Chagas AC, Calvo E, Kopecký J, Kotsyfakis M, Pedra JH. The tick protein sialostatin L2 binds to annexin A2 and inhibits NLRC4-mediated inflammasome activation. Infect Immun. 2016. [Epub ahead of print] PMID: 27045038.

11.  Nikolskaia O Thekisoe O, Dumler JS, Grab DJ. Lamp for detection of the 5.8s rRNA-internal transcribed spacer 2 gene found in Trypanosoma brucei gambiense. Am J Trop Med Hyg [in press].

12.  Chikeka I, Matute AJ, Dumler JS, Woods CW, Mayorga O, Reller ME. Use of peptide ELISA followed by IFA to document Ehrlichia chaffeensis as a cause of febrile illness in Nicaragua. J Clin Microbiol 2016; 54:1581-1585.PMC4879277.

13.  Wurtz N, Dasch G, Papa A, Reusken C, Van Doornum GJ, Hukic M, Rollin PE, Di caro A, Leparc-Goffard I, Leroy EM, Landini MP, Sekeyova Z, Dumler JS, Tolou H, Bădescu D, Meyer H, Marti NB, Calistri P, Parolin C, Palù G, Christova I, Heinzen RA, Reynes JM, Maurin M, Raoult D. Survey of laboratory-acquired infections in the world in biosafety level 3 and 4 laboratories. Clin Microbiol Infect Dis [in press].

14.  Paris DH, Dumler JS. State of the art of diagnosis of rickettsial diseases: the use of blood specimens for diagnosis of scrub typhus, spotted fever group rickettsiosis, and murine typhus. Curr Op Infect Dis [in press].

15.  Nikolskaia OV, Thekisoe OM, Dumler JS, Grab DJ. Loop-mediated isothermal amplification for detection of the 5.8S ribosomal ribonucleic acid internal transcribed spacer 2 gene found in Trypanosoma brucei gambiense. Am J Trop Med Hyg. 2016 [in press].

Profile

Current Research Interests:

Our laboratory studies the functions of members of the carcinoembryonic antigen (CEA) gene family, known as pregnancy specific glycoproteins (PSGs). PSGs are expressed by the placenta of rodents, and primates including humans, which share the type of placentation in which maternal blood is in direct contact with the embryo. PSGs are secreted into the maternal circulation in increasing amounts until term and are the mostabundanttrophoblastic proteins in maternal blood during human pregnancy. Low PSG concentrations in serum correlate with several pregnancy pathologies suggesting that they are important for successful pregnancy. We are using molecular, cell biology and immunology techniques to understand the function of the 17 murine and of the 10 human pregnancy specific glycoprotein family members. We have generated several human and murine recombinant PSGs for our studies. We found that PSGs regulate the secretion of cytokines in vivo. Most importantly, we have shown that members of the human PSG family activate the anti-inflammatory cytokine transforming growth factor beta 1 (TGF-b1) resulting in an increase in the number of T-cells with regulatory function. TheassociationbetweenPSG1andTGF-bsuggeststhatPSGsplayaroleinthewell-established beneficial effects ofpregnancy in patientssuffering fromautoimmunediseases such asmultiplesclerosis, rheumatoid arthritis, uveitis and psoriasis. Therefore we are exploring whether administrationofPSG1could be used as anoveltherapeutic agentin diseases related toundesiredimmuneactivation using animal models. In addition, we have characterized the receptor for several PSGs and found that they induce endothelial tube formation and the secretion of vascular endothelial growth factor, an important modulator of angiogenesis. Therefore, our studies indicate that PSGs are involved in two processes that are essential for pregnancy success: the establishment of the fetal-maternal blood supply and the regulation of the immune responses to the semi-allogeneic fetus.

Complete List of Published Work in MyBibliography:   http://www.ncbi.nlm.nih.gov/sites/myncbi/gabriela.dveksler.1/bibliography/41145838/public/?sort=date&direction=ascending

Education

• A.B. Cornell University, 1954

• M.D. New York University, 1958

Current Research Interests

Interferons are regulators of cell growth and differentiation. Our studies indicate that interferons induce reversion of H-ras-transformed cells by increasing the expression of the gene for the extracellular enzyme, lysyl oxidase. We are currently investigating the regulation of the expression of this gene.

Selected Publications

Friedman Robert M., Yeh Annie, Gutman Pablo, Contente Sara, and Kenyon Kaylene: Reversion by Deletion of transforming oncogene following Interferon-beta and Retinoic Acid Treatment. Journal of Interferon and Cytokine Research 17:647-651, 1997.

Friedman, Robert M.: I Listened to my Grass Roots, But Heard Only Murmurs of Discontent. Cytokine and Growth Factor Reviews, Vol. 8, 2:101, 1997.

Friedman, Robert M.: Foreword.  Journal of Interferon and Cytokine Research 17:Supplement 1:S1 (1997).

Contente Sara, Kenyon Kaylene, Sriraman Priya, Subramanyan Savitri, and Friedman Robert M.: Epigenetic inhibition of lysyl oxidase transcription after transformation by ras oncogene. Molecular and Cellular Biochemistry 194:79-91, 1999.

Naniche Denise, Yeh Annie, Eto Danelle, Manchester Marianne, Friedman Robert M., and Oldstone Michael B.A: Evasion of Host Defenses by Measles Virus: Wild-Type Measles Virus Infection Interferes with Induction of Alpha/Beta Interferon Production. Journal of Virology 74:7478-7484, 2000.

Contente Sara, Attard Frank A., Yeh Tze-Jou Annie, Buchhagen  Dorothy L., & Friedman Robert M.: Deregulated Expression of Interferon Regulatory Factor- 1 in Oncogene-Transformed Mouse Fibroblasts. Journal of Interferon & Cytokine Research 23: 639-647, 2003.

Attard Frank A., Contente Sara, Yeh Tze-Jou Annie, Buchhagen Dorothy L., & Friedman Robert M.: Mechanisms of Deregulation of IFN Regulatory Factor-1 in ras-Transformed Fibroblasts. Journal of Interferon & Cytokine Research 25: 418-423, 2005.

Yeh Annie Tze-Jou, Contente Sara, & Friedman Robert M.: Transformation of Revertant Murine Cells by 5-Azacytidine Results in Rapid Inhibition of Lysyl Oxidase Expression. Acta Microbiologica et Immunologica Hungarica 52:433-442 (2005).

Contente Sara, Attard Frank A., & Friedman Robert M.: Identification of Proteins Immunologically Related to Interferon Regulatory Factor 1 That Bind with Interferon Regulatory Factor Element. Journal of Infectious Dis. 194 (Suppl. 1):S27-32 (2006)

Friedman Robert M.: On the Discovery of Interferon. J.Interferon & Cytokine Research. 27: 175-179 (2007)

Profile

Professor and Vice Chair of Pathology
Professor of Emerging and Infectious Diseases
Email: barbara.knollmann-ritschel@usuhs.edu

Education

• Bachelor of Science, Biochemistry, University of Cincinnati, Cincinnati, OH, 1984-1998
• Doctor of Medicine, University of Cincinnati, Cincinnati, OH, 1988-1993
• Internship, Transitional, National Naval Medical Center, Bethesda, MD, 1993-1994
• Residency, Pathology Anatomic Pathology/Clinical Pathology, National Capitol Consortium, Bethesda, MD, 1994-1998

Dr. Perl received his undergraduate degree from Columbia University and his medical training at the State University of New York, Downstate Medical Center. He then completed postgraduate training in Anatomic Pathology and Neuropathology at Yale University, after which he served for two years as a pathologist in the U.S. Public Health Service, stationed at the Centers for Disease Control in Atlanta. He later served on the faculty of the Brown University Medical School and then the University of Vermont College of Medicine. At the University of Vermont, he began working on Alzheimer’s disease and other age-related neurodegenerative disorders. In 1986, Dr. Perl joined the Mount Sinai School of Medicine in New York, where for 24 years he served as Director of the Neuropathology Division and Professor of Pathology, Psychiatry and Neurosciences. In 2010, Dr. Perl was joined the as a Professor in the Department of Pathology at the USUHS. As the director of the CNRM's Neuropathology Core, he has established a state-of-the-art neuropathology laboratory dedicated to research on the acute and long-term effects of traumatic brain injury among military personnel. He recently became involved in investigations on the long-term effects of repeated head trauma in former NFL football players and other athletes in collaboration with the Boston University Center for the Study of Traumatic Encephalopathy. Dr. Perl has won numerous awards for his research as well as his role as a medical educator.

Uniformed Services University of the Health Sciences
Department of Pathology
Building B, Room 3138
4301 Jones Bridge Rd.
Bethesda, MD 20814

Profile

Current Research Interests

The goal of our laboratory is to develop a detailed and integrated model of the immunologic parameters that mediate both protein-specific and polysaccharide-specific in vivo Ig isotype production both to intact bacteria and bacterial vaccines, using the mouse as the model host. A wide range of cellular methodologies are employed including mouse immunizations, bacterial culture, ELISA, flow cytometry, magnetic and electronic cell sorting, adoptive transfer, immunohistochemistry, in vitro cell culture, antibody and other protein purifications, dendritic cell and macrophage isolation and propagation, and antigen presentation assays. Molecular approaches include extensive use of knockout and transgenic mice including creation of new mouse strains, genotyping, and "Real-time" RT-PCR for measurement of cytokine- and chemokine- specific mRNA. Biochemical approaches include exosome isolation, and conjugate vaccine construction.

Selected Publications

Sen, G, Khan, A. Q., Chen, Q., and Snapper, C. M. 2005. In vivo humoral immune responses to isolated pneumococcal polysaccharides are dependent on the presence of associated TLR ligands. J. Immunol. 175:3084.

Khan, A. Q., Sen, G., Guo, S., Witte, O. N., Snapper, C. M. 2006. Induction of CD4+ T cell-dependent IgG anti-polysaccharide (PS) responses to intact Streptococcus pneumoniae or to a soluble pneumococcal PS-protein conjugate is more heavily dependent on Btk-mediated BCR signaling than anti-protein responses. Infect. Immun. 74:1419.

Sen, G., Chen, Q., and Snapper, C. M. 2006. Immunization of aged mice with a pneumococcal conjugate vaccine when combined with an unmethylated CpG-containing oligodeoxynucleotide restores defective IgG anti-PPS14 responses and PspA-specific CD4+ T cell priming to young adult levels. Infect. Immun. 74:2177.

Chen, Q., Sen, G., and Snapper, C. M. 2006. Endogenous IL-1R1 is critical for cognate, but not non-cognate, CD4+ T cell help for induction of both type 1 and type 2 humoral immunity in response to intact Streptococcus pneumoniae. J. Immunol. 177:6044.

Colino, J., and Snapper, C. M. 2007. Dendritic cell derived exosomes express a Streptococcus pneumoniae capsular polysaccharide type 14 cross-reactive antigen that induces protective immunoglobulin responses against pneumococcal infection in mice. Infect. Immun. 75:220.

Profile

Education

• M.D., Northwestern University Medical School, 1969

Selected Publications

Mani H, Shilo K, Galvin JR, Stocker JT, Franks TJ. Spectrum of Precursor and Invasive Neoplastic Lesions in Type 1 Congenital Pulmonary Airway Malformation: Case Report and Review of the Literature. Histopathology 2007 51(4):561-5.

Stocker JT, Husain AN. Cystic Lesions of the Lung in Children - Classifications and Controversies. European Respiratory Monograph 2007, Volume 12, Monograph #39, 1-20.

Stocker JT. Clinical and Pathologic Differential Diagnosis of Selected Potential Bioterrorism Agents of Interest to Pediatric Health Care Providers. Clin Lab Med 26 (2006)329-344.
 
Agrons GA, Stocker JT, Markowitz RI, Courtney SE. Lung Disease in Premature Neonates: Radiologic-Pathologic Correlation. RadioGraphics 2005:25(4) 1047-73.
 
Pham TT, Bernirschke K, Masliah E, Stocker JT, Yi ES. Congenital Pulmonary Airway Malformation (Congenital Cystic Adenomatoid Malformation) with Multiple Extrapulmonary Anomalies: Autopsy Report of a Fetus at 19 Weeks of Gestation. Pediatr Develop Pathol 2004;7:661-666.
 
Mani H, Suarez E, Stocker JT. The Morphologic Spectrum of Infantile Lobar Emphysema: A Study of 33 Cases. Pediatric Respiratory Reviews 2003;83:S319-326.

Stocker JT. Congenital Pulmonary Airway Malformation : a new name for and an expanded classification of congenital cystic adenomatoid malformation of the lung. Histopathology 2002 41;(supplement 2) 424-430.

Stocker JT and Dehner LP. Editors, Pediatric Pathology. Volumes 1 and 2. 2nd Edition. Lippincott/Williams and Wilkins, Philadelphia 2001:1-1520.
 
Stocker JT. Hepatic Tumors in Children. Clinics in Liver Disease 2001;5:259-281.
 
Conran RM, Stocker JT. Extralobar pulmonary sequestration with frequently associated congential cystic adenomatoid malformation, type 2: report of 50 cases. Pediatric and Developmental Pathology 1999 Sept-Oct;2(5):454-63.
 
White FV, Dehner LP, Biegel JA, Belchis DA, Conard K, Davis MM, Stocker JT, Zuppan CW, Perlman EJ. Congenital disseminated malignant rhabdoid tumor. A distinct clinicopathologic entity demonstrating abnormalities of chromosome 22q11. Am J Surg Path 1999;23:249-256.
 
Hartman A, Stocker JT, Moriarty R. A 7-Week-Old Boy with Respiratory Congestion (clinical conference). J Pediatr 1998;133:457-462.
 
Husain AN, Siddiqui N, Stocker JT. Pathology of arrested lung development in post-surfactant bronchopulmonary dysplasia. Human Pathology 1998;29:710-717.
 
Agrons GA, Rosado de Christenson ML, Kirejczyk WM, Conran RM, Stocker JT. Pulmonary inflammatory pseudotumor; radiologic features. Radiology 1998;206:511-8.
 
Stocker JT and Mosijczuk AD. Handling the pediatric tumor. Editorial AM J Clin Pathol 1998;109(Suppl 1)S1-S3.
 
Stocker JT. An approach to handling pediatric liver tumors. Am J Clin Pathol 1998;109(Suppl 1)S67-S72.
 
Frazier AA, Rosado-de-Christenson, Stocker JT, Templeton PA. Intralobar sequestration: Radiologic-pathologic correlation. RadioGraphics 1997;17:725-745.
 
Selby DM, Stocker JT. Focal peliosis hepatis. Pediatr Pathol & Lab Med 1995;15:589-596.

Stocker JT. Hepatoblastoma. Seminars in Diagnostic Pathology 1994;11 (2):136-143.
 
Selby DM, Stocker JT, Waclawiw MA, Hitchcock CL, Ishak KG. Infantile hemangioendothelioma of the liver. Hepatology 1994;20:39-45.
 
Rosado-de Christianson M and Stocker JT. Extralobar sequestration: Radiologic-pathologic correlation. Radiographics 1993;13:425-441.
 
Zangwill BC and Stocker JT. Congenital Cystic Adenomatoid Malformation Within an Extralobar Pulmonary Sequestration. Pediatric Pathology 1993;13:309-315.
 
Conran R, Stocker JT, Ishak KG, Hitchcock CL, Waclawiw MA. Hepatoblastoma: The prognostic significance of histologic type. Pediatric Pathology 1992; 12:167-184.
 
Selby D, Stocker JT, and Ishak KG. Angiosarcoma of the Liver in Children. Pediatric Pathology 1992;12:485-498.

Stocker JT. Hepatic tumors in children. In Suchy FJ, editor, Liver Disease in Children. Mosby. St. Loius, 1994, p. 901-929.

Stocker JT. Congenital and developmental diseases. In Dail DH and Hammar SP, editors, Pulmonary Pathology, Second Edition, Springer Verlag, New York, 1994, pp 155-190.

Stocker JT and Dehner LP. Acquired neonatal and pediatric diseases. In Dail DH and Hammar SP, editors, Pulmonary Pathology, Second Edition, Springer Verlag, New York, 1994, pp 191-254.

Clouse MN, Moran CA, Stocker JT. Mixed epithelial-mesenchymal tumors. In Saldana MJ, editor, Pathology of Pulmonary Disease, J.B. Lippincott Company, Philadelphia, 1994, pp 617-630.

Stocker JT and Dehner LP. Editors, Pediatric Pathology. Volumes 1 and 2. Lippincott Publishing Co., Philadelphia 1992:1-1409.

McPherson T and Stocker JT. The Pediatric Autopsy. In: Pediatric Pathology. Edited by JT Stocker and LP Dehner, Lippincott Publishing Co., Philadelphia. 1992:3-14.

Waldstein G, Keiper R, Stocker JT. The eye. In: Pediatric Pathology. Edited by JT Stocker and LP Dehner. Lippincott Publishing Co., Philadelphia. 1992:465-490.

Stocker JT. The Respiratory Tract. In: Pediatric Pathology. Edited by JT Stocker and LP Dehner, Lippincott Publishing Co., Philadelphia. 1992:505-574.

Chandra R, Stocker JT. The Liver. In: Pediatric Pathology. Edited by JT Stocker and LP Dehner, Lippincott Publishing Co., Philadelphia. 1992:703-790.

Education

• B.A.(with honors), Psychology, University of Virginia, Charlottesville, VA, 1969
• M.D., University of Virginia Medical School, Charlottesville, VA 22908, 1973

Current Research Interests:

T cell function in lupus, immology of graft-vs-host disease and in vivo immunomodulation.

Selected Publications

Via CS, Shustov A, Rus V, Lang T, Nguyen P, Finkelman FD. In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL. J. Immunol. 167:6821-6826, 2001.

Rus V, Atamas SP, Shustova V, Luzina IG, Selaru F, Magder LS, Via CS. Expression of cytokine- and chemokine-related genes in peripheral blood mononuclear cells from lupus patients by cDNA array. Clin. Immunol.102:283-90, 2002.

Via CS, Nguyen P, Niculescu F, Papadimitriou J, Hoover D, Silbergeld EK. Low dose exposure to inorganic mercury accelerates disease and mortality in acquired murine lupus. Environ. Health Perspect. 111:1273-7, 2003.

Lang TJ,Nguyen P, Papadimitriou J, Via CS. Increased severity of murine lupus in female mice is due to enhanced expansion of pathogenic T cells.J. Immunol. 171:5795-801, 2003.

Puliaev R, Nguyen P, Finkelman F, Via CS. Differential requirements for interferon-in CTL maturation in acute GVHD. J. Immunol. 173:910-919, 2004.

Grader-Beck T, Casciola-Rosen L, Lang T, Rosen A, Via CS. Apoptotic splenocytes drive the autoimmune response to poly (ADP-ribose) polymerase 1 in a murine model of lupus. J. Immunol. 178:95-102, 2007.

Rus V, Nguyen V, Puliaev R, Puliaeva I, Zernetkina V, Luzina I, Papadimitriou JC, Via CS. T cell TRAIL promotes murine lupus by sustaining CD4 T cell help for B cells and inhibiting CD8 cytotoxic T lymphocyte activity. J. Immunol. 178(6):3962-72, 2007.