Regulation and Function of Tissue Kallikrein

描述(申请人提供)：这项研究的目的是研究组织激肽释放酶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，组织激肽释放酶基因或蛋白的传递通过抗氧化、抗凋亡、抗炎和血管生成作用来保护心脏、肾脏和大脑的器官免受损害。这些结果表明激肽释放酶是心血管疾病基因和干细胞联合治疗的理想多效剂。因此，我们假设组织激肽释放酶基因转移或激肽释放酶基因修饰的间充质干细胞(TK-MSC)植入可通过抑制细胞凋亡、促进新生血管和心肌细胞再生在心脏修复中发挥更好的作用。1)研究组织激肽释放酶对大鼠心肌梗死后血管生成、动脉生成和心室重塑以及内皮细胞迁移、生长和毛细血管形成的影响及其信号机制；2)确定组织激肽释放酶是否不依赖于激肽形成而直接通过蛋白分解激活激肽B2受体，从而预防急性心肌梗死后激肽原缺乏大鼠的心肌细胞凋亡、炎症和心功能障碍；3)确定TK-MSCs对急性心肌梗死后大鼠心功能的活性和作用以及对心肌细胞凋亡和炎症的旁分泌作用；4)探讨移植TK-MSCs通过促进心肌梗死后心力衰竭大鼠心脏新生血管形成和心脏再生对心脏修复和重塑的影响。我们的长期目标是开发一种新的治疗策略，使用激肽释放酶基因和基于细胞的疗法来修复和再生受损的心肌。这项研究将产生新的和重要的信息，为开发预防心力衰竭的治疗方案提供动力。 项目简介：我们的目标是研究组织激肽释放酶在急性和慢性心肌梗死动物模型心脏保护中的分子机制。我们的长期目标是开发一种新的治疗策略，使用激肽释放酶基因和基于细胞的治疗方法修复和再生受损的心肌。这项研究将产生重要的信息，为开发预防心功能不全和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.