Mitochondrial K+ Channels and Cardioprotection

线粒体 K 通道和心脏保护

• 批准号: 8788535
• 负责人: Paul S Brookes
• 金额: $ 24.66万
• 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/8788535
• 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; Myocardial Ischemia; 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）：我们的研究计划的总体目标是阐明内源性和其他防御缺血性灌注（IR）伤害的机制，并利用这些知识来开发针对心脏病和中风等IR疾病状况的新疗法。许多心脏保护策略似乎是必要的和足够的保护性信号传导效应器上在线粒体钾通道上收敛的。但是，这些渠道的身份和调节仍然存在争议。迄今为止，我们发表的研究以及本文包含的令人兴奋的初步数据将我们的重点引向了一种新型的线粒体K+通道，该通道是保护所需的，并且以前尚未与保护性信号有关。值得注意的是，该通道的不存在似乎产生了代谢表型。我们还确定了一类新型的内源通道调节剂。在此提案中，AIM 1将表征渠道及其在心脏保护中的作用，AIM 2将调查之间的联系 通道和心脏代谢以及AIM 3将通过内源信号研究其调节。我们将使用各种最先进的技术，包括线粒体（孤立的线粒体内膜）和Seahorse XF方法论的斑块夹来评估心肌细胞生物能力。该双PI建议借鉴了两个研究者的专业知识（Brookes-线粒体生物学，代谢筛查，心脏病生理学； Nehrke -ION通道，小鼠遗传学，线粒体生理学）。我们的生产性轨道记录（3年内由该项目资助的8篇原始研究文章和3条评论）赋予了这3个目标的完成可能会产生有关此渠道的关键信息的很高可能性，这是一个新颖的潜在药物目标。