FGF2 IN VASCULAR DISEASE

描述（改编自研究者摘要）：成纤维细胞生长 已假设成纤维细胞生长因子（FGF）在血管内皮细胞生长因子（VEGF）的表达中起关键作用。 发展和对伤害的反应。 试图测试这些假设， 体内产生的结果不完整或不一致。 的 申请人提出使用小鼠嵌合体方法来测试这些假设 这使得他们能够通过直接测量基因在体内的作用， 比较能或不能表达FGF 2或FGFR 1的细胞的行为。 结合对FGF 2过表达的影响的直接评估， FGF 2失活，这种嵌合体方法将允许研究者 确定FGF 2和FGFR 1在血管发育中的作用， 血管对损伤的反应和成人新血管的形成。 嵌合体分析还将允许测试FGF 2作用于细胞的假设。 直接在合成它的细胞内，通过“内分泌”途径， 这一途径对以下效应有重要作用： 体内FGF 2。 通过将这些结果与正在进行的嵌合体分析相结合， PDGF的作用，申请人将能够建立一个一致的数据 这一套将使人们有可能清楚地区分作用， 每个基因都在发挥作用。 在具体目标1中，申请人计划使用转基因 过表达FGF 2的小鼠，以确定是否存在FGF限制 血管对损伤的反应 这些研究将检验以下假设： 对血管损伤的反应程度部分受到 组织中可用的FGF的量。 在具体目标2中，申请人将 使用FGF 2敲除小鼠来确定FGF 2在新生血管形成中的作用 和血管对损伤的反应。 申请人将检验假设 FGF 2在成人病理中起着更重要的作用， 细胞损伤，释放细胞内FGF 2。 在具体目标3中， 申请人将使用FGF 2敲除小鼠的嵌合体分析来确定 FGF 2是否在体内部分地作为自分泌/内分泌生长因子起作用。 这将通过确定FGF 2失活是否具有细胞毒性来完成。 体内自主表型。 Specific Aim 3旨在使用嵌合体 分析FGFR 1敲除小鼠以确定和定量 FGFR 1在血管发育中的作用 申请人将专注于发展 和心血管系统的成熟。 具体目标5旨在 使用FGFR 1敲除小鼠的嵌合体分析来确定和定量 FGFR 1在新生血管形成和血管对损伤的反应中的作用。 的 申请人将检验FGFR 1调节两个过程的假设 重要的血管病理学：最初的促有丝分裂刺激 细胞和细胞移动到内膜和/或 新生血管形成

DESCRIPTION (Adapted from Investigator's Abstract): Fibroblast Growth Factor (FGF) has been hypothesized to play critical roles in vascular development and response to injury. Attempts to test these hypotheses in vivo have produced results which are incomplete or inconsistent. The applicants propose to test these hypotheses using a mouse chimera approach which allows them to quantitate the role of a gene in vivo by directly comparing the behavior of cells which can or cannot express FGF2 or FGFR1. Combined with a direct evaluation of the effect of FGF2 overexpression and of FGF2 inactivation, this chimera approach will allow the investigator to determine the roles of FGF2 and FGFR1 in blood vessel development and in vascular response to injury and the formation of new vessels in adults. Chimera analysis will also allow for testing the hypothesis that FGF2 acts directly within the cell that synthesizes it, via an "intracrine" pathway, and that this pathway makes a significant contribution to the effects of FGF2 in vivo. By combining these results with an ongoing chimera analysis of the role of PDGF, the applicant will be able to build a consistent data set that will make it possible to clearly distinguish between the role that each gene plays. In Specific Aim 1 the applicant plans to use transgenic mice which overexpress FGF2 to determine whether availability of FGF limits vascular responses to injury. These studies will test the hypothesis that the magnitude of response to vascular injury is limited, in part, by the amount of FGF available in the tissue. In Specific Aim 2 the applicant will use FGF2 knockout mice to determine the role of FGF2 in neovascularization and vascular response to injury. The applicant will test the hypothesis that FGF2 plays a more significant role in adult pathologies which produce cell injury which releases intracellular FGF2. In Specific Aim 3 the applicant will use chimera analysis of FGF2 knockout mice to determine whether FGF2 acts, in part as an autocrine/intracrine growth factor in vivo. This will be done by determining whether FGF2 inactivation has a cell autonomous phenotype in vivo. Specific Aim 3 is designed to use chimera analysis of FGFR1 knockout mice to determine and quantitate the role of FGFR1 in vascular development. The applicant will focus on the development and maturation of the cardiovascular system. Specific Aim 5 is designed to use chimera analysis of FGFR1 knockout mice to determine and quantitate the role of FGFR1 in neovascularization and vascular response to injury. The applicant will test the hypothesis that FGFR1 regulates two processes important for vascular pathologies: the initial mitogenic stimulation of cells and the movement of cells into the intima and/or sites of neovascularization.