Role of HSPG in VEGF Binding to KDR

说明书(申请人摘要)：一种新的治疗实验策略 人心肌缺血是用血管生成生长因子诱导的 新生血管。这种方法是基于最近的研究结果，这些发现表明，在 成人心脏血管生成生长因子编码基因及其表达 受体在缺血心肌周围区域表达，但在水平上 这不足以提供稳健的抵押形成。 给予血管生成生长因子可被视为一种放大 心肌对缺血的正常反应。血管内皮细胞生长 血管内皮生长因子(VEGF)是正常心脏的主要血管生成因子 目前正在进行开发，并将其用于治疗性血管生成 临床评价。 血管内皮生长因子与两种高亲和力内皮细胞受体KDR和Flt1结合。这个 血管内皮生长因子与KDR的相互作用依赖于其他细胞表面分子，在 特别是硫酸乙酰肝素蛋白多糖(NSPG)。很少的信息是 HSPG允许生长因子结合的机制可用。 我的申请提出了澄清这些机制的三个具体目标。 特定目标1测试HSPG与KDR相互作用的假设，以便 促进受体二聚化和血管内皮生长因子结合。拟议中的实验 建立在之前获得的支持这一假设的结果的基础上。特定的 目的2旨在鉴定与血管内皮生长因子结合有关的蛋白多糖 KDR。建议进行实验以测试已知的蛋白多糖是否 负责；或者，如果不是，负责纯化蛋白质并鉴定其氨基酸 酸序列。具体目标3旨在测试相关的HSPG 参与血管内皮生长因子诱导的信号转导事件。这项研究的基本原理 涉及从文献中得出的最新信息，表明 HSPG参与细胞反应的信号转导途径 它们的细胞外环境。

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.