Caveolae, mitochondria, and cardiac protection.

小凹、线粒体和心脏保护。

• 批准号: 7656910
• 负责人: Hemal H Patel
• 金额: $ 37.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-14 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656910
• 关键词: Accounting; Address; Adenoviruses; Adult; Affect; Animals; Arts; Binding; Biochemical; Cardiac; Cardiac Myocytes; Caveolae; Caveolins; Cell membrane; Cessation of life; Connexin 43; Coupling; Cytoplasm; Data; Enzymes; Event; Gene Transfer; Generations; Goals; Heart; Hypoxia; Injury; Intervention; Ischemia; Ischemic Preconditioning; Knockout Mice; Linear Models; Lipids; Mediating; Mediator of activation protein; Membrane; Mitochondria; Mitochondrial Proteins; Modality; Molecular Biology; Mus; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Myocardium; Oxidation-Reduction; Oxygen; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phenotype; Phosphorylation; Post-Translational Protein Processing; Protein translocation; Proteins; Reactive Oxygen Species; Receptor Activation; Receptor Protein-Tyrosine Kinases; Reperfusion Injury; Reperfusion Therapy; Reporting; Resistance; Role; Sarcolemma; Signal Transduction; Small Interfering RNA; Solutions; Structural Protein; Techniques; Transgenic Mice; Transgenic Organisms; Wild Type Mouse; Work; caveolin-2; caveolin-3; design; in vivo; insight; mitochondrial dysfunction; novel; overexpression; preconditioning; prevent; protein complex; public health relevance; receptor; response; src-Family Kinases; therapeutic development; trafficking

DESCRIPTION (provided by applicant): Myocardial ischemia/reperfusion injury is mediated by mitochondrial dysfunction in which damaged mitochondria utilize oxygen at reperfusion for the generation of reactive oxygen species (ROS) rather than energy. ROS have destructive potential. The most beneficial experimental intervention thus far identified for preventing reperfusion injury is ischemic preconditioning (IPC), which occurs when the myocardium is exposed to brief ischemia-reperfusion events prior to lethal ischemia-reperfusion. Previous work has evaluated single parallel pathways that produce IPC utilizing a linear model of membrane receptor activation leading to cardiac protection; however, no single, unifying mechanism has been proposed for IPC to account for its temporal efficiency (i.e., rapid coupling of plasma membrane to mitochondria) and spatial 3-dimensionality (i.e., simultaneous activation of numerous pathways). An emerging idea in signal transduction (i.e., the existence of multi-protein complexes organized in discrete cellular compartments with dynamic potential) suggests a possible solution to this temporal/spatial conundrum of IPC. Two membrane structural proteins, caveolin-3 (Cav-3) and connexin43 (Cx43), exist in dynamic membrane microenvironments, and provide spatial organization to multi-protein complexes in lipid- rich or gap junctional microdomains of the plasma membrane. Little is known regarding Cav-3 and Cx43 interaction and trafficking in the preconditioned myocardium and the effect of post-translational modifications of these proteins on cardiac protection. Our data suggest a close association of caveolae, caveolin, Cx43, and mitochondria and a possible role for this association in IPC. The aims will address the following specific hypotheses: 1: The post-translational modification of caveolin and Cx43 induced by IPC optimizes caveolae/mitochondria interaction to reduce deleterious ROS generated during ischemic-reperfusion injury. 2: Caveolin and Cx43 are essential for IPC-induced interaction of caveolae and mitochondria. 3: Overexpression of caveolin/Cx43 can augment the interaction of caveolae and mitochondria to mimic IPC. The long-term goal of this work is to identify novel signaling mechanisms relevant to cardiac protection and determine the molecules critical in coordinating a multitude of signaling networks in producing a preconditioning phenotype. PUBLIC HEALTH RELEVANCE Injury form a heart attack is lethal and results in death. Certain proteins found in the heart control the degree of injury. It is the goal of this study to discover key proteins involved in protection against a heart attack injury so that drugs can be appropriately designed.

描述（由申请人提供）：心肌缺血/再灌注损伤是通过线粒体功能障碍介导的，线粒体功能障碍损坏的线粒体在再灌注时利用氧气来产生活性氧（ROS）而不是能量。 ROS具有破坏性的潜力。到目前为止，预防再灌注损伤的最有益的实验干预措施是缺血性预处理（IPC），它发生在心肌暴露于短暂的缺血再灌注事件之前，发生在致命性缺血 - 再生灌注之前。先前的工作已经评估了使用膜受体激活的线性模型产生IPC的单个平行途径，从而导致心脏保护。但是，没有提出任何单一的统一机制来解释其时间效率（即，质膜与线粒体快速耦合）和空间3二维（即同时激活众多途径）。信号转导中的一个新兴思想（即，在具有动态电位的离散细胞室中组织的多蛋白络合物的存在）表明，可能解决了IPC的时间/空间障碍的解决方案。两种膜结构蛋白Caveolin-3（CAV-3）和connexin43（CX43）存在于动态膜微环境中，并为脂质富含脂质的或间隙连接的微域中的多蛋白质复合物提供空间组织。关于CAV-3和CX43的相互作用以及在预处理的心肌中的交互以及这些蛋白质后修饰对心脏保护的影响，知之甚少。我们的数据表明，Caveolae，Caveolin，CX43和线粒体的密切关联，以及该关联在IPC中的可能作用。目的将解决以下特定假设：1：由IPC诱导的小窝蛋白和CX43的翻译后修饰优化了小窝/线粒体相互作用，以减少在缺血性重新灌注损伤期间产生的有害ROS。 2：小窝蛋白和CX43对于Caveolae和线粒体的相互作用至关重要。 3：小窝蛋白/CX43的过表达可以增加小窝和线粒体与模拟IPC的相互作用。这项工作的长期目标是确定与心脏保护相关的新型信号传导机制，并确定在协调许多信号网络时至关重要的分子，以产生预处理表型。公共卫生相关性伤害形成心脏病发作是致命的，导致死亡。在心脏中发现的某些蛋白质控制损伤程度。这项研究的目的是发现针对心脏病损伤的保护涉及的关键蛋白质，以便可以适当设计药物。