Mitochondrial K+ Channels and Cardioprotection

线粒体 K 通道和心脏保护

基本信息

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
项目类别：
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

项目摘要

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）：我们研究项目的总体目标是阐明针对缺血再灌注（IR）损伤的内源性和其他保护机制，并利用这些知识来开发治疗 IR 疾病的新疗法，例如心脏病发作和中风。许多心脏保护策略似乎都集中在线粒体钾通道上，作为保护信号传导的必要且充分的效应器。然而，这些渠道的身份和监管仍然存在争议。我们迄今为止发表的研究以及本文中包含的令人兴奋的初步数据，将我们的注意力集中在保护所需的新型线粒体 K+ 通道上，并且之前并未涉及保护性信号传导。值得注意的是，缺乏该通道似乎会产生代谢表型。我们还发现了一类新型的内源性通道调节剂。在该提案中，目标 1 将描述该通道及其在心脏保护中的作用，目标 2 将研究通道之间的联系通道和心脏代谢，Aim 3将研究其内源信号的调节。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 Seahorse XF 方法来评估心肌细胞生物能。这项双 PI 提案借鉴了两位研究人员的专业知识（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）。我们富有成效的跟踪记录（三年内由该项目资助的 8 篇原创研究文章和 3 篇评论）表明，完成这 3 个目标将很有可能产生有关该通道的关键信息，该通道是心脏保护的新型潜在药物靶点。