Regulation and Function of Tissue Kallikrein

描述（由申请人提供）：本研究的目的是探讨组织激肽肽在正常和转基因动物心肌梗死后心脏保护中的作用和分子机制。我们最近的研究表明，组织激肽激酶基因或蛋白的传递通过抗氧化、抗凋亡、抗炎和血管生成等作用，保护心脏、肾脏和大脑免受器官损伤。这些结果表明，钾激肽素是一种多效性药物，是基因和干细胞联合治疗心血管疾病的理想药物。因此，我们假设组织钾likrein基因传递或钾likrein修饰的间充质干细胞（TK-MSC）植入通过抑制细胞凋亡和促进新生血管和心肌细胞再生，在心脏修复中具有优越的益处。研究目的：1)研究组织激肽肽对大鼠心肌梗死后血管生成、动脉生成、心室重构以及内皮细胞迁移、生长和毛细血管形成的影响及其信号机制；2)确定组织激肽激酶是否通过蛋白水解直接激活激肽B2受体，而不依赖激肽的形成，以防止激肽原缺乏大鼠急性心肌梗死后心肌细胞凋亡和炎症及心功能障碍；3)测定大鼠急性心肌梗死后TK-MSCs的活力、对心功能的影响及其对心肌细胞凋亡和炎症的旁分泌作用；4)通过促进梗死后心力衰竭大鼠的新生血管和心脏再生，确定移植TK-MSCs对心脏修复和重构的影响。我们的长期目标是开发一种新的治疗策略，用于心肌修复和损伤心肌的再生，使用kallikrein基因和细胞为基础的治疗。这项研究应该产生新的和重要的信息，为制定预防心力衰竭的治疗方案提供动力。

DESCRIPTION (provided by applicant): The objective of this study is to investigate the role and molecular mechanisms of tissue kallikrein in cardiac protection after myocardial infarction in normal and genetically modified animals. Our recent studies have shown that tissue kallikrein gene or protein delivery protects against organ damage in the heart, kidney and brain through anti- oxidative, anti-apoptotic, anti-inflammatory and angiogenic effects. These results indicate that kallikrein is a pleiotropic agent ideal for combined gene and stem cell therapies for cardiovascular diseases. Therefore, we hypothesize that tissue kallikrein gene delivery or kallikrein modified-mesenchymal stem cell (TK-MSC) implantation provides superior benefits in cardiac repair by inhibiting apoptosis and promoting neovascularization and cardiomyocyte regeneration. We intend to fulfill the following specific aims: 1) determine the effect and signaling mechanisms of tissue kallikrein on angiogenesis, arteriogenesis and ventricular remodeling in rats after myocardial infarction, and on migration, growth and capillary tube formation in endothelial cells; 2) determine whether tissue kallikrein directly activates kinin B2 receptors via proteolysis, independent of kinin formation, to prevent cardiomyocyte apoptosis and inflammation and cardiac dysfunction in kininogen- deficient rats after acute myocardial infarction; 3) determine the viability and effects of TK-MSCs on cardiac function as well as their paracrine effects on cardiomyocyte apoptosis and inflammation in rats after acute myocardial infarction; 4) determine the effects of graft TK-MSCs on cardiac repair and remodeling by promoting neovascularization and cardiac regeneration in rats with post-infarction heart failure. Our long-term goal is to develop a novel therapeutic strategy for myocardial repair and regeneration of damaged myocardium using kallikrein gene and cell-based therapies. This study should generate new and important information to provide the impetus for developing therapeutic regimens in the prevention of heart failure. Project Narrative: Our objective is to investigate the molecular mechanisms of tissue kallikrein in cardiac protection in animal models with acute and chronic myocardial infarction. Our long-term goal is to develop a novel therapeutic strategy for myocardial repair and regeneration of damaged myocardium using kallikrein gene- and cell-based therapies. This study should generate important information to provide the impetus for developing therapeutic regimens in the prevention of cardiac dysfunction and heart failure.