Regulation and Function of Tissue Kallikrein

组织激肽释放酶的调节和功能

• 批准号: 7820918
• 负责人: JULIE CHAO
• 金额: $ 5.14万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820918
• 关键词: Acute; Acute myocardial infarction; Adult; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antihypertensive Agents; Antioxidants; Apoptosis; Apoptotic; Attenuated; Blood Vessels; Blood capillaries; Blood flow; Bone Marrow; Brain; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Survival; Cell Therapy; Chronic; Endothelial Cells; Enzymes; Fibrosis; Functional disorder; Funding; Gene Delivery; Genes; Genetic; Genetically Modified Animals; Goals; Grant; Growth; Healed; Heart; Heart Hypertrophy; Heart failure; Human; Hypertrophy; Hypotension; Hypoxia; Infarction; Inflammation; Injury; Ischemia; Ischemic Stroke; Isoproterenol; Kallikrein-Kinin System; Kidney; Kidney Diseases; Kininogenase; Kininogens; Kinins; Knockout Mice; MAP Kinase Gene; Mediating; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Modeling; Modification; Molecular; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Nitric Oxide; Norway; Organ; Oxidative Stress; Prevention; Property; Proteins; Proteolysis; Rattus; Regulation; Renal function; Reperfusion Therapy; Research; Resistance; Rodent; Role; Signal Pathway; Signal Transduction; Stem cells; Testing; Therapeutic; Tissue Kallikrein; Transgenic Mice; Treatment Protocols; Tube; Vascular Endothelial Growth Factors; Ventricular Remodeling; angiogenesis; base; blood pressure regulation; capillary; cell type; chemokine; cytokine; healing; heme oxygenase-1; human tissue; implantation; improved; innovation; insight; migration; neovascularization; novel; novel therapeutics; overexpression; paracrine; pressure; prevent; receptor; repaired; stem cell therapy

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.

描述（由申请方提供）：本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质递送通过抗氧化、抗凋亡、抗炎和血管生成作用保护心脏、肾脏和大脑免受器官损伤。这些结果表明，激肽释放酶是一个多效性药物的理想组合基因和干细胞治疗心血管疾病。因此，我们假设组织激肽释放酶基因递送或激肽释放酶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血管形成和心肌细胞再生在心脏修复中提供了上级益处。本研究的主要目的是：1）探讨组织激肽释放酶对心肌梗死后血管新生、动脉形成、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）确定组织激肽释放酶是否通过蛋白水解直接激活激肽B2受体，而不依赖于激肽形成，预防急性心肌梗死后激肽原缺乏大鼠的心肌细胞凋亡和炎症以及心功能障碍; 3）确定TK-MSCs的活力和对急性心肌梗死后大鼠心脏功能的影响以及它们对心肌细胞凋亡和炎症的旁分泌作用; 4）观察移植TK-MSCs对心肌梗死后心力衰竭大鼠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，利用激肽释放酶基因和细胞为基础的治疗损伤心肌的心肌修复和再生。这项研究应该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。 项目叙述：我们的目的是研究组织激肽释放酶在急性和慢性心肌梗死动物模型中的心脏保护作用的分子机制。我们的长期目标是开发一种新的治疗策略，利用激肽释放酶基因和细胞为基础的治疗方法来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。