Elucidation of the molecular mechanisms that regulate inflammation in the central nervous system (CNS) is critical to our understanding of a broad spectrum of diseases, including multiple sclerosis, Alzheimer's, and Parkinson's. These diseases are responsible for significant morbidity and mortality, and new prevention and treatment approaches are urgently needed. This proposal builds on our recent finding that glia maturation factor (GMF), a highly conserved protein unique to the brain, serves as an important immune modulator by promoting the production and secretion of pro-inflammatory cytokines leading to the activation of microglia, the antigen presenting cells in the brain. The Human Genome Sequence Consortium has identified the gene of GMF in chromosome 14. In this proposal, we will study experimental autoimmune encephalomyelitis (EAE), the standard animal model for multiple sclerosis, with the hypothesis that GMF contributes to the pathogenesis of EAE. This research will include investigations on the already available GMF knockout mice, wild type mice, and GMF transgenic mice (in the final stages of development) in which GMF transgene will be reintroduced in GMF knockout mice under the influence of astrocyte-specific GFAP promoter. This will provide, for the first time, a unique opportunity to study the pathogenesis of EAE in the contrasting settings of no GMF, normal amount of GMF, and high expression of GMF.
AIM I : To study the effects of GMF on the two major signal transduction cascades involved in CNS inflammation and immune processes, namely, the p38 MAP kinase and JAK/STAT pathways. We will utilize cultured brain cells, astrocytes, microglia and oligodendroglia, derived from GMF knockout versus wild type mice.
AIM II : To study the role of GMF in the pathophysiology of EAE and to establish that the absence of GMF mitigates the severity of the disease. (A) GMF knockout and wild type mice will be challenged with the proper antigen to induce EAE. The development and the histopathology of the brain and spinal cord at various stages of the disease will be compared. (B) To evaluate the expression profiles of cytokines and the free radical generating mediators during the progression of EAE in the brain, spinal cord and in isolated mononuclear cells. Knowledge obtained from this study can also be applied to degenerative diseases of the brain where microglial activation plays an important role, such as Alzheimer's and Parkinson's. ? ?
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