Role of mitochondria in cardiac ischemia

线粒体在心肌缺血中的作用

• 批准号: 8038650
• 负责人: Peifeng Li
• 金额: $ 38.68万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038650
• 关键词: Animal Model; Apoptosis; Apoptotic; Cardiac; Cardiac Myocytes; Cell Proliferation; Cells; Cessation of life; Crista ampullaris; Cytochromes; Cytosol; Dominant-Negative Mutation; Dynamin; Energy Supply; Functional RNA; Functional disorder; Genes; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Ischemia; Kidney; Lead; Maintenance; Mammalian Cell; Mediating; MicroRNAs; Mitochondria; Molecular; Morphogenesis; Myocardial Infarction; Organelles; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Physiology; Play; Prevention; Process; Proteins; Publications; RNA Interference; Regulation; Reperfusion Therapy; Reporting; Role; Serum; Skeletal Muscle; Structure; Testing; Therapeutic; Work; base; heart function; innovation; mortality; neoplastic cell; novel; overexpression; prevent; prohibitin; response

DESCRIPTION (provided by applicant): Summary Heart failure is a leading cause of mortality worldwide. Myocardial infarction has been proved to be the most common cause of heart failure. The effective therapeutic strategies need to be developed for the prevention and treatment of myocardial infarction. Apoptosis is a type of death form in myocardial infarction. In order to maintain the heart intact in both structure and function, it is necessary to prevent apoptosis so that the heart does not lose cardiomyocytes. It is well known that cardiomyocytes are enriched in mitochondria. Mitochondria on one hand supply energy for the heart function, they on the other hand participate in the initiation of apoptosis. The most recent studies have revealed that mitochondrial abnormal fission plays a critical role in the regulation of apoptosis. However, the role of mitochondrial fission in the cardiac diseases has been less studied. Furthermore, the molecular regulation of mitochondrial fission in cardiomyocytes remains largely unknown. Our long term goal is to study the role of mitochondria in cardiac pathophysiology. Prohibitin is a cardiac abundant protein. The function of prohibitin in the heart has not yet been clarified. miRNAs are involved in the regulation of cardiac physiology and pathology, but it is unknown whether miRNAs are able to regulate mitochondrial fission machinery. We have made observations clearly showing that prohibitin and miRNA levels are altered in response to oxidative stress and cardiac ischemia. Furthermore, prohibitin can prevent mitochondrial fission and apoptosis in cardiomyocytes. We hypothesize that miRNA and prohibitin constitute an axis in the regulation of mitochondrial fission and apoptosis in the heart. Studies under aim-1 and aim-2 will characterize whether prohibitin can be targeted by the miRNA, and their roles in mitochondrial fission and apoptosis. Studies under aim-3 will explore the molecular mechanism by which prohibitin regulate mitochondrial fission and apoptosis. Studies under aim-4 will test whether prohibitin can influence myocardial infarction induced by ischemia/reperfusion. This proposed project will not only help understand mitochondrial fission and its molecular regulation in the heart, but also can lead to further studies to develop the innovative approaches for the interventional treatment of apoptosis-related cardiac diseases such as myocardial infarction. PUBLIC HEALTH RELEVANCE: Project Narrative Heart failure is a leading cause of mortality worldwide. Myocardial infarction has been proved to be the most common cause of heart failure. The effective therapeutic strategies need to be developed for the prevention and treatment of myocardial infarction. Apoptosis is a type of death form in myocardial infarction, it is thus necessary to prevent apoptosis in the heart. Cardiomyocytes are enriched in mitochondria. However, mitochondria on one hand supply energy for the heart function, they on the other hand participate in the initiation of apoptosis. The most recent studies have revealed that mitochondrial abnormal fission plays a critical role in the regulation of apoptosis. Our proposed project is expected to reveal the role of mitochondrial fission in the cardiac apoptosis. The obtained results can lead to further studies to develop the innovative approaches for the interventional treatment of apoptosis-related cardiac diseases such as myocardial infarction.

描述(由申请人提供)： 心力衰竭是世界范围内导致死亡的主要原因。心肌梗死已被证明是心力衰竭最常见的原因。预防和治疗心肌梗死需要制定有效的治疗策略。细胞凋亡是心肌梗死的一种死亡形式。为了保持心脏在结构和功能上的完整，有必要防止细胞凋亡，使心脏不会失去心肌细胞。众所周知，心肌细胞富含线粒体。线粒体一方面为心脏功能提供能量，另一方面参与细胞凋亡的启动。最近的研究表明，线粒体的异常分裂在细胞凋亡的调控中起着至关重要的作用。然而，线粒体分裂在心脏疾病中的作用研究较少。此外，心肌细胞线粒体分裂的分子调控在很大程度上仍不清楚。我们的长期目标是研究线粒体在心脏病理生理学中的作用。Prohibitin是一种心脏富含的蛋白质。禁忌素在心脏中的作用尚不清楚。MiRNAs参与心脏生理和病理的调节，但目前尚不清楚miRNAs是否能够调节线粒体的分裂机制。我们的观察清楚地表明，在氧化应激和心肌缺血的情况下，抑制素和miRNA的水平会发生变化。此外，抑制素还能阻止心肌细胞线粒体的分裂和凋亡。我们假设miRNA和Prohibitin在心脏线粒体分裂和凋亡的调控中构成了一个轴。在AIM-1和AIM-2下的研究将表征禁止素是否可以被miRNA靶向，以及它们在线粒体分裂和凋亡中的作用。在AIM-3下的研究将探索禁止素调控线粒体分裂和凋亡的分子机制。根据AIM-4进行的研究将测试禁止素是否会影响缺血/再灌流引起的心肌梗死。这一项目不仅将有助于了解线粒体分裂及其在心脏中的分子调控，而且可以导致进一步的研究，为心肌梗死等与细胞凋亡相关的心脏疾病的介入治疗开发创新的方法。 公共卫生相关性： 项目叙述心力衰竭是世界范围内死亡的主要原因。心肌梗死已被证明是心力衰竭最常见的原因。预防和治疗心肌梗死需要制定有效的治疗策略。细胞凋亡是心肌梗死的一种死亡形式，因此有必要防止心脏中的细胞凋亡。心肌细胞富含线粒体。然而，线粒体一方面为心脏功能提供能量，另一方面参与细胞凋亡的启动。最近的研究表明，线粒体的异常分裂在细胞凋亡的调控中起着至关重要的作用。我们提出的计划有望揭示线粒体分裂在心脏细胞凋亡中的作用。研究结果可为心肌梗死等与细胞凋亡相关的心脏疾病的介入治疗提供新的研究方向。