FIBROBLAST GROWTH FACTOR 1 IN VASCULAR PATHOBIOLOGY

描述：（改编自研究者的摘要）。血管生成是许多疾病的特征，包括糖尿病视网膜病变、类风湿关节炎、动脉粥样硬化和实体肿瘤的生长和转移。成纤维细胞生长因子（FGF）家族的原型是血管生成生长因子之一，直接作用于血管细胞诱导增殖和细胞迁移。这项应用的长期目标是阐明由FGF-1启动的信号通路，希望最终揭示抗血管生成治疗的新策略。这项研究得到了当前拨款的支持，主要关注的是一种FGF信号分子和Src酪氨酸激酶的底物。研究结果表明：(1)接触蛋白是一种丝状肌动蛋白（F-actin）交联蛋白，可被Src下调；（ii）酪氨酸磷酸化与内皮细胞的迁移有关；（iii） Src和接触蛋白是FGF-1介导的形状改变和细胞迁移所必需的；（iv）酪氨酸磷酸化解除了接触蛋白二聚化的调节。这些结果表明，接触蛋白是一种重要的信号分子，它将FGF信号传递到细胞骨架，并参与了细胞形状变化和细胞迁移的离散途径。本应用程序的目的是研究细胞内接触作用的机制。詹博士假设(i)接触蛋白的f -肌动蛋白交联活性对细胞迁移、形状改变和内皮细胞分化（管形成）很重要；（ii）虽然接触信号通路与有丝分裂反应的信号通路不同，但它与FGF-1的其他早期信号通路相结合；（iii）由FGF-1诱导的细胞边缘的接触易位对细胞迁移很重要。为了验证这些假设，詹博士将研究接触二聚化和f -肌动蛋白交联的机制。然后，他将研究接触蛋白活性在fgf -1介导的细胞形状改变、细胞运动和内皮细胞分化中的功能作用。此外，他将研究早期FGF-1信号分子在接触蛋白酪氨酸磷酸化中的作用。最后，他将剖析响应于FGF-1的细胞内皮层再分配的机制，并探索可能的靶向皮层进入细胞前沿的细胞内分子。预计这些研究的结果将描述导致细胞迁移和有丝分裂的信号通路。

DESCRIPTION: (adapted from the investigator's abstract). Angiogenesis is a feature of many diseases, including diabetic retinopathy, rheumatoid arthritis, atherogenesis, and the growth and metastasis of solid tumors. The prototypes of the fibroblast growth factor (FGF) family are among the angiogenic growth factors that act directly on vascular cells to induce proliferation and cell migration. The long-term goal of this application is to elucidate the signaling pathway initiated by FGF-1 in the hope to ultimately reveal new strategies for anti-angiogenic therapy. This research, which is being supported by the current grant, has focused on cortactin, a FGF signaling molecule and a substrate of Src tyrosine kinase. The results of the research demonstrate that (i) cortactin is a filamentous actin (F-actin) cross-linker and can be down-regulated by Src; (ii) tyrosine phosphorylation of cortactin is implicated in the migration of endothelial cells; (iii) Src and cortactin are required for FGF-1 mediated shape change and cell migration, and (iv) tyrosine phosphorylation deregulates cortactin dimerization. These results indicate that cortactin is an important signaling molecule that transmits the FGF signals to the cytoskeleton and is involved in a discrete pathway for shape change and cell migration. The objective of this application is to investigate the mechanism by which cortactin acts within cells. Dr. Zhan hypothesizes that (i) the F-actin cross-linking activity of cortactin is important for cell migration, shape change and endothelial cell differentiation (tube formation); (ii) while the cortactin signal pathway is distinct from that for the mitogenic response, it is integrated with other early signaling events of FGF-1; and (iii) translocation of cortactin into the leading edge of cells induced by FGF-1 is important for cell migration. To test these hypotheses, Dr. Zhan will study the mechanism for cortactin dimerization and F-actin cross-linking. He will then examine the functional role of the activity of cortactin in FGF-1-mediated cell shape change, cell motility and endothelial cell differentiation. In addition, he will examine the role of the early FGF-1 signaling molecules in the tyrosine phosphorylation of cortactin. Finally, he will dissect the mechanism for the redistribution of cortactin within cells in response to FGF-1 and explore possible intracellular molecules that target cortactin into the leading edge of cells. It is anticipated that the results from these studies will delineate the signal pathways that lead to cell migration and mitogenesis.