Pathological Consequences of the Plasminogen System

描述（由申请人提供）：本提案的长期目标是利用体内模型确定纤维蛋白溶解系统及其抑制剂在生理和病理生理过程中的功能和机制。纤溶系统在止血中的作用，通过纤溶蛋白催化纤维蛋白降解的能力，已经在体外和体内模型中得到了广泛的研究。许多细胞表面纤维蛋白溶解系统组分受体的鉴定暗示纤溶蛋白在细胞迁移事件中起作用。编码纤维蛋白溶解系统成分的基因存在单一和多重缺陷的小鼠的可用性导致了对这些蛋白质在许多生理和病理事件中的作用的直接分析。先前的研究已经证明，缺乏这些蛋白质对动脉粥样硬化、肺纤维化、皮肤伤口愈合、肿瘤生长和血管生成有显著影响。由于PAl-1缺乏对血管损伤/修复、肿瘤生长、血管生成和伤口愈合的影响，本应用程序中描述的研究将集中在以下研究：

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to identify functions and determine mechanisms of the fibrinolytic system, and its inhibitors, in physiological and pathophysiological processes utilizing in vivo models. The contribution of the fibrinolytic system in hemostasis, through the capacity of plasmin to catalyze degradation of fibrin, has been extensively studied in both in vitro and in vivo models. The identification of receptors for components of the fibrinolytic system on a number of cell surfaces implicates plasmin as playing a role in cell migratory events. The availability of mice with single and multiple deficiencies of genes encoding components of the fibrinolytic system have resulted in direct analyses of the role of these proteins in a number of physiological and pathological events. Previous studies have demonstrated dramatic effects of deficiencies of these proteins in atherosclerosis, pulmonary fibrosis, skin wound healing, tumor growth, and angiogenesis. Due to the impact of a PAl-1 deficiency on vascular injury/repair, tumor growth, angiogenesis, and wound healing, studies described in this application will focus on the following studies: 1.) Since a PAl-1 deficiency diminishes angiogenesis, the effects on endothelial cell proliferation, migration, sprouting, directed migration, apoptosis, and expression of angiogenic regulatory molecules will be studied utilizing PAl-1-/- endothelial cells. 2.) Determine whether the PAl-1 effects on angiogenesis are mediated through alterations in cell adhesion, inhibition of plasminogen activator function, or uPA-mediated cell signaling by generating mice expressing mutated PAl-1 proteins and challenging these mice with models with phenotypes associated with an angiogenic response. 3.) Further characterize functional deficits of endothelial cells derived from mice described in Aim 2 utilizing analyses described in Aim 1.