The Rel/NF-KB family of transcription factors play pivotal roles in inflammation and immunity. The long-term goal of our research is to elucidate the mechanisms of Rel/NF-kB action in autoimmune diseases. This proposal is based on our recent discovery that c-Rel-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE), and are unable to develop a strong TH1 type response to self-myelin antigens. The goal of this proposal is to elucidate the mechanisms of c-Rel action in animal models of multiple sclerosis. A major challenge to study the roles of transcription factors in autoimmune diseases is that they are often expressed by a variety of cell types. In the case of c-Rel, it is expressed not only by cells of the immune system, but also by cells of target organs such as brain and spinal cord. The roles of c-Rel in different cell types must be established before a comprehensive understanding of c-Rel action in autoimmunity can be achieved. We hypothesize that c-Rel expressed by immune cells and neural cells may play different roles in EAE: c-Rel expressed by immune cells orchestrates the activation and effector function of inflammatory cells leading to tissue injury, whereas c-Rel expressed by neural cells protects them from inflammation-induced cell death, presumably by activating anti-apoptotic genes. To test these hypotheses, we will study the roles of c-Rel in 1) activation of myelin-specific T cells, 2) formation of inflammatory lesions, and 3) death of inflammatory and neural cells in EAE. The roles of c-Rel expressed by different cell types will be dissected using transgenic adoptive transfer models and bone-marrow chimeric models. Information generated from these studies may not only help elucidate the mechanisms of c-Rel action in EAE but also aid in developing a general strategy to study the roles of transcription factors in autoimmune diseases. Novel strategies targeting Rel/NF-kB may then be developed to treat or prevent the autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI050059-01
Application #
6362043
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Ridge, John P
Project Start
2001-09-01
Project End
2006-06-30
Budget Start
2001-09-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$320,963
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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