Mitochondrial K+ Channels and Cardioprotection

线粒体 K 通道和心脏保护

• 批准号: 8652105
• 负责人: Paul S Brookes
• 金额: $ 26万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652105
• 关键词: Ablation; Acetylation; Acids; Address; Affect; Agonist; Anesthetics; Bioenergetics; Biological Assay; Biology; Biotin; Budgets; Caenorhabditis elegans; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cell physiology; Cellular Stress; Cessation of life; Data; Development; Disease; Drug Targeting; Enzymes; Epoxide hydrolase; Exhibits; Funding; Gene Family; Genes; Genetic; Genus Hippocampus; Goals; Health; Heart failure; Immunologics; In Situ; In Vitro; Injury; Inner mitochondrial membrane; Investigation; Ion Channel; Ischemia; Ischemic Preconditioning; Knock-out; Knockout Mice; Knowledge; Link; Lipids; Lysine; Mediating; Metabolic; Methodology; Methods; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Myocardial; Myocardial Infarction; NADH dehydrogenase (ubiquinone); Neurons; Normal Cell; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Post-Translational Protein Processing; Potassium Channel; Probability; Property; Protein Isoforms; Proteins; Publishing; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Resistance; Role; Signal Transduction; Stroke; Techniques; Testing; Thallium; heart metabolism; in vivo; inhibitor/antagonist; interest; mouse model; novel; patch clamp; preconditioning; programs; screening; sensor; therapeutic target; tool; voltage

DESCRIPTION (provided by applicant): The overall goal of our research program is to elucidate endogenous and other mechanisms of protection against ischemia-reperfusion (IR) injury, and to exploit this knowledge to develop new therapies for IR disease conditions such as heart attack and stroke. Many cardioprotective strategies appear to converge on mitochondrial potassium channels as necessary and sufficient effectors of protective signaling. However, the identity and regulation of these channels remains controversial. Our published research to date, and exciting preliminary data contained herein, have directed our focus to a novel mitochondrial K+ channel that is required for protection and has not previously been implicated in protective signaling. Notably, absence of this channel appears to yield a metabolic phenotype. We have also identified a novel class of endogenous channel modulators. In this proposal, Aim 1 will characterize the channel and its role in cardioprotection, Aim 2 will investigate links between the channel and cardiac metabolism, and Aim 3 will study its regulation by endogenous signals. We will use a variety of state-of-the -art techniques, including patch-clamp of mitoplasts (isolated mitochondrial inner membranes), and Seahorse XF methodology to assess cardiomyocyte bioenergetics. This dual-PI proposal draws on the expertise of both investigators (Brookes - mitochondrial biology, metabolic screening, cardiac patho-physiology; Nehrke - ion channels, mouse genetics, mitochondrial physiology). Our productive track-record (8 original research articles and 3 reviews funded by this project in 3 years) imparts a high probability that the completion of these 3 aims will yield critical information about this channel, which is a novel potential drug target for cardioprotection.

描述(由申请人提供)：我们研究计划的总体目标是阐明防止缺血-再灌注(IR)损伤的内源性和其他保护机制，并利用这一知识开发针对心脏病发作和中风等IR疾病的新疗法。许多心肌保护策略似乎都集中在线粒体钾通道上，作为保护信号的必要和充分的效应器。然而，这些渠道的身份和监管仍然存在争议。到目前为止，我们发表的研究和本文中包含的令人兴奋的初步数据将我们的重点放在了一个新的线粒体K+通道上，该通道是保护所必需的，以前还没有涉及到保护性信号。值得注意的是，缺乏这一通道似乎会产生代谢表型。我们还发现了一类新的内源性通道调节剂。在这项提案中，目标1将描述该通道及其在心脏保护中的作用，目标2将调查 通道和心脏代谢，目标3将研究其内源性信号的调节。我们将使用各种最先进的技术，包括线粒体膜片钳(分离的线粒体内膜)和海马XF方法来评估心肌细胞的生物能量学。这一双PI方案利用了两位研究者的专业知识(Brookes-线粒体生物学、代谢筛查、心脏病理生理学；Nehrke离子通道、小鼠遗传学、线粒体生理学)。我们卓有成效的记录(3年内由该项目资助的8篇原始研究文章和3篇综述)表明，这3个目标的完成将产生关于该通道的关键信息，这是一个新的潜在的心脏保护药物靶点。