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WOUND HEALING ANGIOGENESIS

伤口愈合血管生成

基本信息

批准号：
6519868
负责人：
FRANK ISIK
金额：
$ 14.48万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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

项目摘要

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。伤口修复需要血管生成激活纤溶酶促进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系统，它由尿激酶型纤溶酶原激活物(UPA)和组织型纤溶酶原激活物(TPA)，由纤溶酶原激活物抑制物-1(PAI-1)平衡，这限制了纤溶酶的产生和过度的纤溶。机制在体内调节纤溶酶原激活物，以及对纤溶酶原激活系统在伤口愈合血管生成中的作用未定义。 Vitronectin，一种在血浆中发现并沉积在部位的糖蛋白对于组织损伤，在体内没有明确的作用。Vitronectin可以结合游离PAI-1，该复合体可与内皮细胞表面结合 UPA受体，uPAR。对UPAR的竞争决定了平衡在纤溶和抑制之间。鉴于这些监管机制已经在体外证明了，研究人员建议证明Vitronectin调节纤溶酶原激活剂系统在对损伤的反应中的血管生成。缺乏玻璃连蛋白或纤溶酶原激活剂的转基因小鼠系统基因产物在表型上表现正常。调查员的初步数据表明，在体内，Vitronectin作为一种纤溶调节因子，对血管内皮细胞尤其重要迁移。初步数据还首次显示， Vitronectin：PAI-1复合体结合生长因子被认为是重要的用于血管生成。这些数据表明， Vitronectin、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。这个研究人员将在基因靶向的小鼠身上使用伤口愈合模型缺乏Vitronectin、uPA、tPA或uPAR来定义个体玻璃体连结蛋白和PA系统在术后新生血管中的作用组织损伤。