FIBROBLAST GROWTH FACTOR 1 IN VASCULAR PATHOBIOLOGY

描述：(改编自调查人员的摘要)。血管生成是许多疾病的特征，包括糖尿病视网膜病变、类风湿性关节炎、动脉粥样硬化形成以及实体肿瘤的生长和转移。成纤维细胞生长因子家族的原型是直接作用于血管细胞以诱导细胞增殖和迁移的血管生成生长因子。这一应用的长期目标是阐明由成纤维细胞生长因子-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。这项研究得到了目前拨款的支持，重点是皮质蛋白，一种成纤维细胞生长因子信号分子和Src酪氨酸激酶的底物。研究结果表明：(I)Cortactin是一种丝状肌动蛋白(F-actin)交联物，可被Src下调；(Ii)Cortactin的酪氨酸磷酸化与内皮细胞的迁移有关；(Iii)Src和Cortactin是成纤维细胞生长因子-1介导的形状改变和细胞迁移所必需的；以及(Iv)酪氨酸磷酸化解除调节Cortactin的二聚化。这些结果表明，Cortactin是一种重要的信号分子，它将成纤维细胞生长因子信号传递到细胞骨架，并参与形状改变和细胞迁移的离散途径。这项应用的目的是研究皮质素在细胞内的作用机制。詹博士假设：(I)皮质肌动蛋白的F-肌动蛋白交联活性对于细胞迁移、形状变化和内皮细胞分化(管状形成)是重要的；(Ii)尽管皮质肌动蛋白信号通路不同于促有丝分裂反应的信号通路，但它与其他早期信号事件成纤维细胞生长因子-1是整合的；以及(Iii)皮质肌动蛋白移位到由成纤维细胞生长因子-1诱导的细胞前沿对细胞迁移是重要的。为了验证这些假说，詹博士将研究皮质肌动蛋白二聚化和F-肌动蛋白交联的机制。然后，他将研究皮质蛋白的活性在成纤维细胞生长因子-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，他还将研究早期的成纤维细胞生长因子-1信号分子在皮质蛋白酪氨酸磷酸化中的作用。最后，他将剖析反应成纤维细胞生长因子-1的细胞内皮质蛋白重新分布的机制，并探索以皮质蛋白为靶点进入细胞前沿的可能的细胞内分子。预计这些研究的结果将描绘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.