VEGF INDUCED SIGNAL TRANSDUCTION

VEGF 诱导的信号转导

• 批准号: 6514540
• 负责人: BRUCE I TERMAN
• 金额: $ 28.08万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-16 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514540
• 关键词: angiogenesis; angiogenesis inhibitors; biological signal transduction; growth factor receptors; molecular site; phosphorylation; protein protein interaction; protein structure function; protein tyrosine kinase; tissue /cell culture; transfection; vascular endothelial growth factors; vascular endothelium

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.

描述：（申请人的描述） 血管生成（新毛细血管的形成）是重要的 一些正常生理过程的组成部分，包括发育和 伤口愈合。 血管生成也有助于疾病的发生和扩散 疾病，例如在癌症中，血管生成为肿瘤细胞提供 必需营养素，从而有助于肿瘤生长。 一个 抗癌的抗血管生成策略很有吸引力，因为 将靶向内皮细胞并可能避免耐药性 当靶向肿瘤细胞时观察到。 血管内皮生长因子 (VEGF) 已被考虑作为血管生成抑制的靶标 有几个原因：肿瘤细胞的表达因缺乏 VEGF 的作用是针对内皮细胞的，并且阻断 VEGF 的作用将抑制小鼠体内肿瘤的生长。 有关 VEGF 激活的信号转导途径的信息有限。 此前，我们实验室发现了KDR基因，并将其鉴定为一种 VEGF 受体。 KDR 是一种受体酪氨酸激酶，我们已经鉴定出 四个自磷酸化位点。 本申请中提出的实验 都针对两个目标。 首先，我们希望从分子水平上了解 KDR 自磷酸化如何招募细胞信号蛋白。 其次，我们有 设计实验来阐明特定的细胞结果 受体/信号蛋白相互作用。 提出四项具体目标 实现这些目标。 具体目标 1 将确定是否有 除了之前报道的自磷酸化位点之外。 具体的 目标 2 将检验激酶中受体自身磷酸化的假设 域是最大催化活性所必需的。 具体目标 3 已明确 阐明与受体相互作用的信号蛋白 自磷酸化位点。 具体目标 4 旨在澄清 依赖于受体的内皮细胞反应 特定酪氨酸的磷酸化。