Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that afflicts millions of young adults worldwide. Although the etiology is not known, the pathogenesis of MS appears to involve the breakdown of immune self-tolerance leading to inflammatory demyelinating attack on the CNS. Activation of macrophage/microglia, secretion of IL-12, differentiation of encephalitogenic Th1 cells and secretion of IFN gamma is critical events in CNS demyelination. Increased levels of IL-12 in the CNS associate with clinical disease in human and EAE animal model of MS. Inhibition of IL-12/IFN gamma axis prevents the development of EAE. Targeted expression of IL-12 in the CNS resulted spontaneous inflammation and demyelination in GF-IL-12 transgenic mice. PPAR gamma is a nuclear hormone receptor that regulates immune cell activation and inflammation. PPAR gamma agonists have been used for the treatment of diabetes and inflammatory diseases. Our preliminary studies suggested that PPAR gamma regulates IL-12/IFN gamma axis and CNS inflammation and demyelination in SJL/J mice. In this project, we propose to investigate the molecular mechanisms in PPAR gamma regulation of IL 12/IFN gamma axis in CNS demyelination. Using PPAR gamma agonists, 15d-PGJ2 and Ciglitazone, we will define the mechanisms in the PPAR gamma regulation of JAK-STAT and NF-kB signaling pathways leading to IL-12 gene expression in microglia and IFN gamma secretion in cells. Using GF-IL-12 transgenic mice we will define the mechanisms in the PPAR gamma regulation of IL-12 signaling leading to IFN gamma gene expression and Th1 differentiation in vitro and in vivo. Using GF-IL-12 transgenic and PPAR gamma heterozygous mice, we will define the role of PPAR gamma in the regulation of IL-12/IFN gamma axis in the pathogenesis of CNS inflammation and demyelination. We believe that this project is novel and will provide new insights on the mechanisms of PPAR gamma regulation of signaling pathways in IL-12/IFN gamma axis in Th1 differentiation in vitro and in CNS demyelination in vivo and new therapeutic agents for the treatment of human MS and other inflammatory autoimmune demyelinating diseases of the CNS. ? ?
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