VEGF INDUCED SIGNAL TRANSDUCTION

描述：(申请人描述) 血管生成(新的毛细血管的形成)是一种重要的 几个正常生理过程的组成部分，包括发育和 伤口愈合。血管生成也有助于血管的发生和扩散。 疾病，例如在癌症中，血管生成为肿瘤细胞提供了 必需的营养物质，从而促进肿瘤的生长。一个 抗癌的抗血管生成策略很有吸引力，因为 会以内皮细胞为靶点，并有可能避免耐药性 靶向肿瘤细胞时观察到。血管内皮生长因子 血管内皮生长因子(VEGF)已被认为是抑制血管生成的靶点 几个原因：它在肿瘤细胞中的表达因缺乏 营养素，血管内皮生长因子的作用是内皮细胞特有的，并阻断 血管内皮生长因子的作用将抑制在老鼠体内生长的肿瘤的生长。 关于血管内皮细胞生长因子激活的信号转导通路的信息有限。 此前，我们的实验室发现了KDR基因，并将其鉴定为 血管内皮生长因子受体。KDR是一种受体酪氨酸激酶，我们已经鉴定 四个自动磷酸化位点。此应用程序中建议的实验 是针对两个目标的。首先，我们希望从分子水平上了解 KDR自动磷酸化如何招募细胞信号蛋白。第二，我们有 设计实验以阐明特定基因的细胞后果 受体/信号蛋白相互作用。提出了四个具体目标来 完成这些目标。具体目标1将决定是否有 除了先前报道的那些外，还有一些自磷酸化位点。特定的 Aim 2将检验一种假说，即该蛋白中的受体自磷酸化 结构域是获得最大催化活性所必需的。具体目标3 阐明与受体相互作用的信号蛋白 自动磷酸化位点。具体目标4旨在澄清 依赖受体的内皮细胞反应 特定酪氨酸的磷酸化。

DESCRIPTION: (Applicant's Description) Anglogenesis (the formation of new blood capillaries) is an important component of several normal physiological processes including development and wound healing. Angiogenesis also contributes to the onset and spread of disease, for example in cancer angiogenesis provides tumor cells with essential nutrients and thus contributes to tumor growth. An anti-angiogenesis strategy for fighting cancer is attractive because this would target endothelial cells and potentially avoid the drug resistance observed when targeting tumor cells. Vascular Endothelial Growth Factor (VEGF) has received consideration as a target for angiogenesis inhibition for several reasons: Its expression by tumor cells is augmented by a lack of nutrients, VEGF's actions are specific to endothelial cells, and blocking VEGF's actions will inhibit the growth of tumors grown in mice. Information on the signal transduction pathways activated by VEGF is limited. Previously, our laboratory discovered the KDR gene and identified it as a receptor for VEGF. KDR is a receptor tyrosine kinase and we have identified four autophosphorylation sites. The experiments proposed in this application are directed at two goals. First, we wish to understand at a molecular level how KDR autophosphorylation recruits cell signaling proteins. Second, we have designed experiments to clarify the cellular consequence of specific receptor/signaling protein interactions. Four Specific Aims are proposed to accomplish these goals. Specific Aim 1 will determine whether there are autophosphorylation sites in addition to the ones reported earlier. Specific Aim 2 will test the hypothesis that receptor autophosphorylation in the kinase domain is required for maximum catalytic activity. Specific Aim 3 is directed at clarifying the signaling proteins which interact with receptor autophosphorylation sites. Specific Aim 4 is directed at clarifying endothelial cellular response which are dependent upon receptor phosphorylation at specific tyrosines.