CNS FIBROBLAST GROWTH FACTORS--ACTIVITY AND REGULATION

最初定义神经营养因子的标准要求 存在可溶性的、可扩散的蛋白质，其在局部细胞中起作用， 维持神经元存活的环境，促进神经突生长， 在最好的情况下，还能增强神经元的再生 一些 然而，像碱性成纤维细胞生长因子这样的分子， 神经营养，但不符合这些标准。 而不是可溶的 并且是可扩散的，这些分子不是传统意义上的分泌， 但定位并停留在细胞表面， 生物惰性形式。 碱性FGF有限的生物利用度 似乎可以调节其活性，并将生长因子隔离在其 作用地点。 因此，它被认为是一种抗肿瘤药物， 时尚，最有可能需要细胞接触，以介导之间的转移 细胞 在目前的提案中，我们将调查这一点可能发挥的作用， 生长因子作为一种神经营养剂，并试图确定 介导其激活的分子机制， 细胞外区室 我们将评估其高 亲和受体调节其活性，并确定是否后 分子中的翻译变化参与调节其 在细胞表面的生物利用度。 提出了克隆策略 如果成功的话，它将识别出 介导生长因子从隔离部位转移到 低亲和力的递送位点，并最终使其高亲和力 受体的

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.