FIBROBLAST GROWTH FACTOR I IN VASCULAR PATHOBIOLOGY

血管生成是许多疾病的特征，包括糖尿病 视网膜病变，类风湿性关节炎，动脉粥样硬化，以及生长和 实体瘤的转移和成纤维细胞的原型膜 生长因子（FGF）家族属于血管生成生长因子， 直接作用于血管细胞以诱导内皮细胞生长， 迁移 虽然本申请的长期目标是阐明 FGF-1启动的信号通路可能最终揭示新的 抗血管生成治疗的策略，直接目标是 表征FGF受体-1（FGFR-10）与皮质激素的相互作用， 最近鉴定的FGF受体和src家族的底物， FGF-1诱导的信号转导途径的潜在成分。 我们将研究这些信号调节剂在FGF-1中的功能， 介导的细胞迁移和增殖， 体内血管生成。 具体来说，我们将识别酪氨酸 皮质激素中的残基，其响应于FGF-1而被磷酸化， 磷酸肽图谱和磷酸氨基酸分析及其功能 将通过定点诱变来研究这些位点。 是 预计这些研究的结果将提供标准， 定义负责酪氨酸的真实激酶 coronin的磷酸化。 虽然我们的初步数据显示， c-src和FGFR-1都能够与coronin结合，我们将 通过研究确定哪种激酶与coronin更相关 体内FGF-1依赖性酪氨酸磷酸化。 一旦 FGFR-1、coronin和c-src之间的相互关系被定义，我们将 进一步启动缺失、定点诱变研究， 参与它们与蛋白质结合的氨基酸序列， 细胞骨架和检查机制负责的共同- coronin和c-src与细胞骨架的定位。 基于 根据这些研究结果，我们将尝试设计一系列 可能干扰相互作用的显性负突变体 在野生型FGFR-1，c=-src和corneum之间。 这些变种人 最终被用来研究它们在FGF-1中的生物学作用， 介导的DNA合成和趋化性，以及它们作为 体内抗血管生成药。

Angiogenesis is a feature of many diseases, including diabetic retinopathy, rheumatoid arthritis, atherogenesis, and the growth and metastasis of solid tumors and the prototype membranes of fibroblast growth factor (FGF) family are among the angiogenic growth factors that act directly on vascular cells to induce endothelial cell growth and migration. While the long-term goal of this application is to elucidate the signaling pathway initiated by FGF-1 which may ultimately reveal new strategies for antiangiogenic therapy, the immediate goal is to characterize the interaction of FGF receptor-1 (FGFR-10) with cortactin, a recently identified substrate for the FGF receptor, and src family and potential components of the FGF-1 induced signal transduction pathway. We will examine the function of these signaling modulators in FGF-1 mediated cell migration and proliferation in vitro and during angiogenesis in vivo. Specifically, we will identify the tyrosine residues in cortactin that are phosphorylated in response to FGF-1 using phosphopeptide mapping and phosphoamino acid analysis and the function of these sites will be studied by site-directed mutagenesis. It is anticipated that the results from these studies will provide criteria to define the authentic kinase(s) responsible for the tyrosine phosphorylation of cortactin. While our preliminary data suggest that both c-src and FGFR-1 are able to associate with cortactin, we will ascertain which is the more relevant kinase for cortactin by studying FGF-1-dependent tyrosine phosphorylation in vivo. Once the interrelationship among FGFR-1, cortactin and c-src are defined, we will further initiate deletion, site-directed mutagenesis studies to dissect the amino acid sequences involved in their association with the cytoskeleton and examine the mechanism responsible for the co- localization of cortactin and c-src with the cytoskeleton. Based on the results from these studies, we will attempt to design a series of dominant negative mutants that may interfere with the interactions between wild-type FGFR-1, c=-src and cortactin. These mutants will ultimately be exploited to study their biological roles in the FGF-1- mediated DNA synthesis and chemotaxis, and their potential as antiangiogenics in vivo.