Growth factor interactions have been shown to regulate the generation of differentiated cells from progenitor cells during CNS development. Similar cellular and molecular interactions are required for repopulation of demyelinated lesions and remyelination in the adult CNS. The proposed studies will test the in vivo roles of platelet-derived growth factor (OPDGF-AA) and fibroblast growth factor 2 (FGF2) in promoting remyelination. In human demyelinating diseases, such as multiple sclerosis, remyelination can lead to recovery of neurologic function of intact axons. However, in multiple sclerosis, remyelination is often limited and so investigating mechanisms to improve remyelination is warranted. Two experimental models of demyelination in mice will be used: murine hepatitis virus A59 (MHV-A59) infection and ingestion of euprizone toxin. Each model produces extensive CNS demyelination followed by spontaneous remyelination. However, the mechanism of demyelination is distinctly different in each model and the lesion environment is distinctly different in each model. Growth factors that are required for remyelination in both models may be universally required for remyelination in murine CNS and may be likely to be required during remyelination in human CNS. In these spontaneously remyelinating models, growth factors that are required for remyelination must already be present at appropriate levels to accomplish successful remyelination. Indeed, we have already show increased expression of PDGF- A and FGF2 mRNA during remyelination after MHV-A59 infection. Thus, the activity of PDGF-AA and FGF2 will be impaired in vivo to test the requirement of these growth factors in mediating specific oligodendrocyte lineage cell responses involved in remyelination. PDGF-AA and FGF2 in vivo activity will be impaired, singly and in combination in each model of demyelination using genetic and pharmacologic tools. Specific in vivo oligodendrocyte lineage cell responses will be elucidated by qualitatively and quantitatively monitoring a) disease severity and time course, b) progenitor cell proliferation, migration, differentiation, and survival, and c) reactive glial cell populations. This detailed understanding of growth factor regulation of remyelination may provide the insight needed to aid in designing therapeutics to improve the capacity for remyelination in multiple sclerosis, and following demyelination associated with traumatic injuries or toxic insults.
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