REGULATION OF GLIAL CELL DEVELOPMENT AND INJURY RESPONSE

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It is well known that growth factors, neurotrophins, cytokines and hormones regulate glial cell function. Alterations in the expression of these factors results in serious changes in cell morphology and molecular expression during CNS injury and disease. The number of factors to be considered is overwhelming. We have chosen to focus on those that we consider to be imperative for glia development and function. Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the etiology of many CNS disorders. It is thought to be involved in both beneficial and cytotoxic actions within an organism: however, little is known with respect to receptor expression. Our proposed studies, therefore, will phenotype the cell population(s) that express TNF receptor in the CNS. Reactive astrocytes and activated microglia are hallmarks of many CNS disorders. The mechanisms that regulate their activation are poorly understood. however, studies in our laboratory have highlighted two cytokines, ciliary neurotrophic factor (CNTF) and TNF-alpha, as playing a pivotal role. We propose therefore, to further examine the involvement of these cytokines in the initial stages of the inflammatory disease process. Platelet-derived growth factor-AA (PDGF- AA) is known to support oligodendrocyte (OL) survival and proliferation. In vivo data suggests OL compete for a limited amount of trophic factor and that PDGF may be a rate limiting factor in determining the number of OL that survive. Recent studies in our laboratory have shown that only cells early within the OL lineage express the PDGF-alpha(r). These findings are extremely important because they reveal that the main cell population in the CNS that is capable of responding to PDGF-AA is the OL: therefore, suggesting a possible therapeutic role for PDGF-AA in demyelinating disorders. We propose to test this hypothesis by providing experimental allergic encephalomyelitis (EAE) mice. mice inflicted with a CNS inflammatory and demyelinating disorder. with PDGF-AA growth factor treatment. Another growth factor that is known to enhance OL survival is neurotrophin-3 (NT-3). Recent studies in our laboratory support the presence of a biologically functional TrkC receptor in cells of the OL lineage. We plan to utilize normal, NT-3 and TrkC knockout mice to determine the potential roles and molecular mechanisms of NT-3 action on glia survival, proliferation and apoptosis in vivo and in vitro. It is well known that CNS disorders resulting from a variety of insults often demonstrate common injury responses. This overlap is observed in many adult and pediatric disorders associated with mental retardation, AIDS neuropathy, ischemia/anoxia, MS, leukodystrophies, head trauma, epilepsy and encephalitis. Our goals will attempt to understand the complex interactions of these factors during CNS development, disease and the injury response. It is our belief that some of these factors are essential during gliogenesis and glial recovery; while others play a detrimental role when expressed at high concentrations during CNS disease.