T cells and B cells are thought to play a critical role in the pathogenesis of Multiple Sclerosis. The proposed research proposal will dissect the functions of the ?-secretase and Notch signaling using the experimental autoimmune encephalomyelitis (EAE) models of MS. The goal is to test the suitability of Notch as a therapeutic target in MS. Our preliminary results demonstrate a profound reduction in the severity of EAE when the mice are treated with a small molecule inhibitor of ?-secretase. In order to dissect the role(s) of ?-secretase and Notch signaling we will utilize T cell and B cell-specific Cre recombinase transgenic mice we will generate conditional knockout mice that lack ?-secretase functions by disrupting Presenilin 1 (the catalytic subunit of ?-secretase);and we wil block Notch signaling by blocking Protein-o-fucosyl transferase 1 (POFUT1) a critical glycosyl transferase required for Notch signaling. We will monitor the development of EAE and examine the mice for changes in the underlying T cell differentiation and effector functions as well as the generation of functional MOG-specific B cell responses that are required for this model of EAE. Our overall goal is to determine how ?-secretase or Notch targeted therapies would regulate the immune response and use these experiments as a proof of principle to further pursue these therapies in MS patients.

Public Health Relevance

Multiple sclerosis is a debilitating autoimmune disease of the central nervous system (CNS). The goal of our research is to understand the function of the Notch signaling pathway in controlling the immune response in the experimental autoimmune encephalomyelitis model (EAE) of MS. The knowledge gained from this research will provide a rationale for Notch-based immunotherapies for treatment of MS and other autoimmune diseases.

National Institute of Health (NIH)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Utz, Ursula
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Methodist Hospital Research Institute
United States
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Raphael, Itay; Nalawade, Saisha; Eagar, Todd N et al. (2015) T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 74:5-17