Martin E. Dorf

Department of Pathology
Harvard Medical School
New Research Bldg., Room 830
77 Avenue Pasteur
Boston, MA 02115
Tel: 617-432-1978
Fax: 617-432-2789
e-mail: dorf@hms.harvard.edu
3 postdoctoral fellows

This laboratory focuses on the mechanisms controlling inflammatory responses especially in the central nervous system. Elevated levels of the proinflammatory cytokine TNFa are noted in multiple sclerosis and its experimental model experimental autoimmune encephalomyelitis (EAE). TNFa promotes production of inflammatory cytokines and chemokines. TNFa is considered to be an important contributor to the pathogenesis of multiple chronic autoimmune and infectious diseases. Most studies of effector T lymphocytes employ cell populations which remain heterogeneous with regard to cytokine production. This can obscure the functional activity of distinct T cell subsets which reside within the heterogeneous population. By single cell cloning of encephalitogenic T cells this laboratory dissects the roles of TNFa and other cytokines in EAE pathogenesis.

Astrocytes are the most abundant cell type in the central nervous system and are activated in multiple sclerosis and EAE lesions. These cells are highly responsive to TNFa and other cytokines and respond by releasing a cascade of chemokines which further amplify inflammatory processes. TNFa signaling occurs through cognate receptors which recruit intracellular adaptor proteins including TRAF2 leading to activation of NF-kB along with other transcription factors. This laboratory investigates the role of TRAF2 in controlling TNF-mediated NF-kB responses. Phosphorylation and polyubiquitination control TRAF2 signal transduction and link this adaptor to downstream kinases. Using a combination of genetic, biochemical, and microscopic approaches we investigate the molecular interactions regulating TRAF2 phosphorylation and the biologic consequences of dephosphorylation.

Papers & Publications:

1. Abromson-Leeman, S., R. Bronson, Y. Luo, M. Berman, R. Leeman, J. Leeman, and M. Dorf. 2004. T-cell properties determine disease site, clinical presentation, and cellular pathology of experimental autoimmune encephalomyelitis. Am J Pathol 165:1519-33.
2. Lee, I., L. Wang, A. D. Wells, M. E. Dorf, E. Ozkaynak, and W. W. Hancock. 2005. Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med 201:1037-44.
3. Li, S., L. Wang, M.A. Berman, and M.E. Dorf. 2006. RNAi screen in mouse astrocytes identifies phosphatases that regulate NF-kB signaling. Mol. Cell 24:497-509.