FGF2 IN VASCULAR DISEASE

描述(摘自《研究人员摘要》)：成纤维细胞生长 成纤维细胞生长因子被认为在血管中起关键作用 发展和对伤害的反应。尝试在以下方面测试这些假设 VIVO产生的结果是不完整或不一致的。这个 申请者建议使用小鼠嵌合体方法来检验这些假设 这使得他们能够通过直接量化基因在体内的作用 比较能够或不能表达FGF2或FGFR1的细胞的行为。 结合直接评估FGF2过表达和 对于FGF2失活，这种嵌合体方法将允许调查者 确定FGF2和FGFR1在血管发育中的作用 成人对损伤的血管反应和新血管的形成。 嵌合体分析还将允许检验FGF2起作用的假设 通过“内分泌”途径，直接在细胞内合成它， 而且这一途径对 体内表达FGF2。通过将这些结果与正在进行的嵌合体分析相结合 对于PDGF的作用，申请者将能够构建一致的数据 这一设置将使我们能够清楚地区分 每个基因都发挥作用。在具体目标1中，申请人计划使用转基因 过量表达FGF2的小鼠以确定成纤维细胞生长因子的可用性是否限制 血管对损伤的反应。这些研究将检验这一假设 对血管损伤的反应程度有限，部分原因是 组织中可用的成纤维细胞生长因子的量。在具体目标2中，申请人将 利用FGF2基因敲除小鼠确定FGF2在新生血管形成中的作用 以及血管对损伤的反应。申请者将检验这一假设 FGF2在成人的病理中起着更重要的作用 细胞损伤，释放细胞内的FGF2。在具体目标3中 申请者将使用FGF2基因敲除小鼠的嵌合体分析来确定 在体内，FGF2是否部分作为自分泌/内分泌生长因子发挥作用。 这将通过确定FGF2失活是否具有细胞来完成 体内的自主表型。《特定目标3》是为使用嵌合体设计的 分析FGFR1基因敲除小鼠的作用并进行定量 FGFR1与血管发育申请者将专注于发展 心血管系统的成熟。专门的目标5旨在 利用FGFR1基因敲除小鼠的嵌合体分析来确定和定量 FGFR1在血管新生和损伤反应中的作用。这个 申请者将检验FGFR1调节两个过程的假设 对血管病理学的重要作用：最初的有丝分裂刺激 细胞和细胞向血管内膜和/或部位的移动 新生血管。

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.