CNS FIBROBLAST GROWTH FACTORS--ACTIVITY AND REGULATION

最初定义神经营养因子的标准要求 存在作用于局部细胞的可溶的、可扩散的蛋白质 维持神经元存活，促进轴突生长的环境， 而且，在最好的情况下，增强神经元的再生。一些人 然而，像碱性成纤维细胞生长因子这样的分子是高度 神经营养，但不符合这些标准。与其说它是可溶的 而且可扩散，这些分子不是经典意义上的分泌， 但被定位并停留在细胞表面，似乎是一种 生物惰性的形式。碱性成纤维细胞生长因子的生物利用度有限 似乎调节了它的活动，并将生长因子隔离在其 行动地点。因此，它被认为是以并列的方式起作用的 时尚，很可能需要细胞接触来协调 细胞。 在目前的提案中，我们将调查这一点可能发挥的作用 生长因子作为神经营养剂发挥作用，并试图识别 从隔离中调节其活化的分子机制 细胞外的隔间。我们将评估其高的作用 亲和力受体调节其活性，并决定是否后 分子中的翻译变化参与调节其 细胞表面的生物利用度。提出了一种克隆策略 当成功时，它将确定 调节生长因子从封存部位转移到 低亲和力部位的递送，并最终达到其高亲和力 受体。

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.