KATP Channel Trafficking and Cardioprotection

KATP 通道运输和心脏保护

基本信息

批准号：
9236252
负责人：
William A Coetzee
金额：
$ 7.94万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9236252
关键词：
Action Potentials Adenosine Adult Arrhythmia Back Biological Assay Biotinylation C-terminal Cardiac Cardiac Myocytes Cause of Death Cell model Cell physiology Cells Cessation of life Complex Confocal Microscopy Coupled Data Defect Dependence Developed Countries Dominant-Negative Mutation Elements Endocytosis Event Family member Functional disorder GLUT4 gene Health Heart Heart Diseases Heart Rate Infarction Injury Ischemia Ischemic Preconditioning Knock-out Knockout Mice Mass Spectrum Analysis Measurement Mediator of activation protein Membrane Proteins Metabolic Molecular Mus Muscle Cells Mutagenesis Myocardial Ischemia Myocardium Pathway interactions Pattern Physiological Protein Family Protein Kinase Proteins Pump Reactive Oxygen Species Recycling Reperfusion Therapy Research Role Signal Pathway Specificity Stress Surface Tamoxifen Tertiary Protein Structure Transcription Factor AP-2 Alpha Transgenic Mice United States Ventricular conditioning density design extracellular heart rhythm inhibitor/antagonist insight mouse model new therapeutic target novel overexpression patch clamp prevent protective effect therapeutic development trafficking

项目摘要

DESCRIPTION (provided by applicant): Heart disease remains the leading cause of death in the United States and other developed countries. Most deaths are associated with cardiac ischemia and arrhythmias. Sarcolemmal KATP channels in the myocardium open with elevated heart rates and during stress conditions, such as cardiac ischemia. Opening of KATP channels modulate the action potential duration and intracellular Ca2+. As such they have an important role in determining contractility, arrhythmias and electrical conduction. It is well established tht KATP channel opening protects the heart during stress. However, a detailed understanding of the KATP channel function during ischemia, reperfusion and ischemic preconditioning is lacking, which hinders the development of therapeutic strategies. Our preliminary data point to novel subcellular localization patterns of KATP channels within the cardiac myocyte. We further find that myocardial ischemia decreases the surface KATP channel density, which reduces the number of channels that are available for cardioprotection. This proposal is driven by our preliminary observations that a) ischemic preconditioning prevents ischemia-induced internalization of KATP channels and that b) the protective effects of ischemic preconditioning on infarct size are abolished in mice with cardiac-specific knockout of the KATP channel subunit, Kir6.2. We hypothesize that enhancing KATP channel surface density through specific subcellular trafficking pathways is an important element of the protective mechanism of ischemic preconditioning. We will investigate molecular mechanisms that stabilize surface KATP channels (Aim 1), cellular processes that regulate internalization (Aim 2) and potential mechanisms to restore the KATP channel surface density during an ischemic insult (Aim 3). The proposed studies will establish a framework in which to understand novel roles of KATP channels in the heart and will provide molecular insights their cardioprotective function during ischemic pre-conditioning.

描述（由申请人提供）：心脏病仍然是美国和其他发达国家的主要死亡原因，大多数死亡与心肌缺血和心律失常在心率升高和应激条件下开放有关。例如心脏缺血时，KATP 通道的开放可调节动作电位持续时间和细胞内 Ca2+，因此它们在确定收缩力、心律失常和电方面具有重要作用。众所周知，KATP 通道开放可在应激期间保护心脏，但缺乏对缺血、再灌注和缺血预适应期间 KATP 通道功能的详细了解，这阻碍了我们的初步数据表明新的治疗策略。我们进一步发现心肌缺血会降低表面 KATP 通道密度，即可用于心脏保护的通道数量。这一提议是由我们的初步观察推动的：a) 缺血预处理可防止缺血诱导的 KATP 通道内化，b) 在心脏特异性敲除 KATP 通道亚基 Kir6 的小鼠中，缺血预处理对梗死面积的保护作用被消除.2.我们认为通过特定的亚细胞运输途径增强KATP通道表面密度是缺血预处理保护机制的重要组成部分我们将研究稳定表面KATP的分子机制。通道（目标 1）、调节内化的细胞过程（目标 2）以及在缺血性损伤期间恢复 KATP 通道表面密度的潜在机制（目标 3）。拟议的研究将建立一个框架，以了解 KATP 通道的新作用。在心脏中，并将在缺血预处理期间提供其心脏保护功能的分子见解。