Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that afflicts more than 300,000 people in the United States alone. Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis. Although the genetic and environmental factors that trigger the disease vary, the common pathological outcome of multiple sclerosis is the destruction of myelin-producing oligodendrocytes and their associated neuronal axons through a process called encephalomyelitis. Development of encephalomyelitis requires coordinated expression of a large number of genes that mediate the activation, differentiation, migration and effector function of inflammatory cells (activated lymphoid and myeloid cells). These include genes that encode pro-inflammatory cytokines, chemokines and cytotoxic enzymes. Expression of these genes is tightly regulated at the transcriptional level by specific transcription factors. Recent studies from several laboratories including ours indicate that, c-Rel, the lymphoid member of the Rel/nuclear factor-:B (Rel/NF-:B) family, is a long sought-after transcriptional regulator of MS and EAE. The goal of this application is to elucidate the cellular and molecular mechanisms through which c-Rel mediates autoimmune encephalomyelitis. The mammalian Rel/NF-:B family consists of five members, each of which is endowed with a distinct set of function not shared by other members, although each member may also perform additional functions common to the family. Thus, unlike other members that are ubiquitously expressed, c-Rel is preferentially expressed by inflammatory cells, and is involved in regulating a special subset of immune responses. The cellular and molecular basis of these c-Rel-specific effects is not well understood. In this proposal, we test the hypotheses that 1) c-Rel orchestrates the development of autoimmune encephalomyelitis by specifying gene expression in inflammatory cells, 2) c-Rel promotes the development of encephalitogenic Th17 cells, and 3) c-Rel:interleukin-23 axis plays a key role in the pathogenesis of autoimmune encephalomyelitis.The proposed studies in this application will not only help elucidate the pathogenic mechanisms of multiple sclerosis but also aid in developing specific strategies to treat or prevent the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050059-07
Application #
7828035
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2001-09-01
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
7
Fiscal Year
2010
Total Cost
$393,750
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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