CNS FIBROBLAST GROWTH FACTORS--ACTIVITY AND REGULATION

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The original criteria defining neurotrophic factors called for the existence of soluble, diffusible proteins which act in a local cellular environment to maintain neuronal survival, promote neurite outgrowth, and, in the best of circumstances, enhance neuronal regeneration. Some molecules like basic fibroblast growth factor, however, are highly neurotrophic, but do not meet these criteria. Rather than being soluble and diffusible, these molecules are not secreted in a classical sense, but localized and remain at the cell surface in what appears to be a biologically inert form. This limited bioavailability of basic FGF appears to regulate its activity and sequester the growth factor at its site of action. Accordingly, it is thought to act in a juxtacrine fashion, most likely requiring cell contact to mediate transfer between cells. In the current proposal, we will investigate the possible role that this growth factor plays as a neurotrophic agent, and attempt to identify the molecular mechanisms that mediate its activation from sequestered extracellular compartments. We will evaluate the role of its high affinity receptor in regulating its activity, and determine whether post translational changes in the molecule are involved in regulating its bioavailability at the cell surface. A cloning strategy is presented which, when successful, will identify the molecular mechanisms that mediate the transfer of the growth factor from sites of sequestration to low affinity sites of delivery, and ultimately to its high affinity receptor.