Role of HSPG in VEGF Binding to KDR

HSPG 在 VEGF 与 KDR 结合中的作用

• 批准号: 6499183
• 负责人: BRUCE I TERMAN
• 金额: $ 29.26万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-05 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6499183
• 关键词: angiogenesis; biological signal transduction; growth factor receptors; human tissue; proteoglycan; receptor binding; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (Applicant's abstract): A new experimental strategy for treating ischemia of the human myocardium is to use angiogenic growth factors to induce neovascularization. This approach is based upon recent findings showing that in the adult heart the genes encoding angiogenic growth factors and their receptors are expressed in areas surrounding ischemic myocardium, but at levels that are insufficient to provide robust formation of collaterals. Administration of angiogenic growth factors can be viewed as an amplification of a normal response of the myocardia to ischemia. Vascular endothelial growth factor (VEGF) serves as a major angiogenic factor in normal cardiac development, and its use in therapeutic angiogenesis is currently undergoing clinical evaluation. VEGF binds to two high affinity endothelial cell receptor, KDR and FLT1. The interaction of VEGF with KDR is dependent upon other cell surface molecules, in particular heparan sulfate proteoglycans (NSPG). Little information is available as to the mechanisms by which HSPGs allow for growth factor binding. My application proposes three Specific Aims for clarifying those mechanisms. Specific Aim 1 tests the hypothesis that HSPGs interact with KDR in order to facilitate receptor dimerization and VEGF binding. The proposed experiments build upon previously obtained results that support this hypothesis. Specific Aim 2 is directed at identifying the proteoglycan involved in VEGF binding to KDR. Experiments are proposed for testing whether a known pro teoglycan is responsible; or if not, for purifying the protein and identifying its amino acid sequence. Specific Aim 3 is directed at testing whether the relevant HSPG participates in VEGF-induced signaling events. The rationale for this study relates to the recent information derived from the literature indicating that HSPGs participate in the signal transduction pathways by which cells respond to their extracellular environment.

描述（申请人摘要）：一种新的实验策略， 人心肌缺血是利用血管生成生长因子诱导 新生血管形成这一做法是基于最近的调查结果，表明，在 成人心脏的基因编码血管生成生长因子及其 受体在缺血心肌周围区域表达，但水平 这不足以提供稳固的侧支形成。 血管生成生长因子的管理可以被视为一种放大 心肌对缺血的正常反应。血管内皮生长 血管内皮生长因子（VEGF）是正常心脏组织中主要的血管生成因子， 开发，其在治疗性血管生成中的应用目前正在进行 临床评价 VEGF与两种高亲和力的内皮细胞受体KDR和FLT 1结合。的 VEGF与KDR的相互作用依赖于其它细胞表面分子， 特别是硫酸乙酰肝素蛋白聚糖（NSPG）。信息很少 关于HSPG允许生长因子结合的机制，目前还没有可用的研究。 我的申请提出了三个具体目标，以澄清这些机制。 具体目标1检验了HSPG与KDR相互作用的假设， 促进受体二聚化和VEGF结合。拟议的实验 建立在先前获得的支持这一假设的结果之上。具体 目的2是鉴定参与VEGF结合的蛋白聚糖， KDR。提出了用于测试已知的蛋白聚糖是否是 负责;或者如果不是，用于纯化蛋白质并鉴定其氨基 酸性序列具体目标3旨在测试相关HSPG是否 参与VEGF诱导的信号传导事件。本研究的基本原理 与最近从文献中获得的信息有关， HSPGs参与细胞应答的信号转导途径， 它们的细胞外环境