WOUND HEALING ANGIOGENESIS

伤口愈合血管生成

• 批准号: 2767173
• 负责人: FRANK ISIK
• 金额: $ 13.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2767173
• 关键词: angiogenesis; burns; cell migration; disease /disorder model; enzyme activity; fibrinogen receptors; fibrinolysis; fibroblast growth factor; gene targeting; genetically modified animals; human tissue; immunocytochemistry; immunoprecipitation; in situ hybridization; intermolecular interaction; laboratory mouse; plasminogen activator; plasminogen activator inhibitors; tissue /cell culture; urokinase; vascular endothelium; vitronectin; western blottings; wound healing

One of the cellular components of normal wound repair is angiogenesis, the formation of new blood vessels. Wound repair angiogenesis requires activation of fibrinolytic enzymes for cellular migration of microvascular endothelial cells through a fibrin matrix. These fibrinolytic enzymes include the plasminogen activator system, which consists of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), balanced by plasminogen activator inhibitor-1 (PAI-1), which limits plasmin generation and excessive fibrinolysis. Mechanisms that regulate plasminogen activators in vivo and the requirement for the plasminogen activator system in wound healing angiogenesis remain undefined. Vitronectin, a glycoprotein found in plasma and deposited at the site of tissue injury, has no defined role in vivo. Vitronectin can bind free PAI-1 , and this complex can bind to the endothelial cell surface receptor for uPA, uPAR. Competition for uPAR determines the balance between fibrinolysis and inhibition. Whereas these regulatory mechanisms have been demonstrated in vitro, the investigators propose to demonstrate that vitronectin modulates the plasminogen activator system in angiogenesis during response to injury. Transgenic mice deficient for vitronectin or the plasminogen activator system gene products appear phenotypically normal. The investigator's preliminary data indicate that in vivo, vitronectin functions as a regulator of fibrinolysis, especially important for endothelial cell migration. The preliminary data also show for the first time that the vitronectin: PAI-1 complex binds growth factors cited to be important for angiogenesis. These data suggest that interaction between vitronectin, the PA system, and growth factors are an important component of endothelial cell response to injury and angiogenesis. The investigator will use a wound healing model in gene-targeted mice deficient in vitronectin, uPA, tPA, or uPAR to define the individual functions for vitronectin and the PA system for neovascularization after tissue injury.

正常伤口修复的细胞成分之一是血管生成， 新血管的形成。 伤口修复血管生成需要 激活纤维蛋白溶解酶，用于细胞迁移， 微血管内皮细胞通过纤维蛋白基质。 这些 纤溶酶包括纤溶酶原激活物系统， 由尿激酶型纤溶酶原激活物（uPA）和组织型纤溶酶原组成 激活剂（tPA），由纤溶酶原激活剂抑制剂-1（派-1）平衡， 这限制了纤溶酶的产生和过度的纤维蛋白溶解。机制 在体内调节纤溶酶原激活物的蛋白质， 纤溶酶原激活物系统在创伤愈合血管生成中的作用 未定义。 玻连蛋白，一种在血浆中发现并沉积在 在体内没有明确的作用。 玻连蛋白可以结合 游离派-1，该复合物可与内皮细胞表面结合 尿激酶型纤溶酶原激活物受体。 uPAR的竞争决定了平衡 纤维蛋白溶解和抑制之间的联系而这些调节机制 已经在体外证明，研究人员建议， 证明玻连蛋白调节纤溶酶原激活物系统 在对损伤的反应过程中的血管生成。 玻连蛋白或纤溶酶原激活物缺陷的转基因小鼠 系统基因产物表现正常。 研究者 初步的数据表明，在体内，玻连蛋白作为一个功能， 纤维蛋白溶解调节剂，对内皮细胞尤其重要 迁移 初步数据还首次显示， 玻连蛋白：派-1复合物结合生长因子被认为是重要的 for angiogenesis血管生成.这些数据表明， 玻连蛋白，PA系统和生长因子是一个重要的 内皮细胞对损伤和血管生成的反应的组成部分。 的 研究人员将在基因靶向小鼠中使用伤口愈合模型 缺乏玻连蛋白、uPA、tPA或uPAR来定义个体 玻连蛋白和PA系统的新血管形成功能， 组织损伤