Mitochondrial Calmodulin Kinase II in Physiology and Disease

线粒体钙调蛋白激酶 II 在生理学和疾病中的作用

基本信息

批准号：
8909894
负责人：
MARK E ANDERSON
金额：
$ 39.69万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-09 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8909894
关键词：
ATP Synthesis Pathway Abbreviations Agonist Automobile Driving Binding Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Calcium/calmodulin-dependent protein kinase Cardiac Myocytes Cardiomyopathies Cell Death Cells Cessation of life Charge Data Disease Dominant-Negative Mutation Enzymes Event Figs - dietary Genes Goals Heart failure Homeostasis Infusion procedures Injury Inner mitochondrial membrane Ion Channel Isoproterenol Knockout Mice Mediating Membrane Membrane Potentials Metabolism Mitochondria Modeling Molecular Molecular Target Mus Myocardial Myocardial dysfunction Myocardium NADH Nature Neonatal Oxidative Phosphorylation Oxidoreductase Pathway interactions Permeability Pharmaceutical Preparations Phosphorylation Physiological Physiology Production Proteins Public Health Reactive Oxygen Species Resistance Role Second Messenger Systems Serine Site Source Stimulus Stress Testing Time Transgenic Organisms Work base biophysical properties calmodulin-dependent protein kinase II clinically relevant effective therapy in vivo innovation knock-down mouse model prevent public health relevance response second messenger therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Heart failure is a major public health problem without adequate therapies. Loss of myocardial Ca2+ homeostasis and mitochondrial Ca2+ overload are fundamental events driving heart failure progression, but no currently available therapies prevent excessive mitochondrial Ca2+ entry. In 2011, after a 50 year search, two groups independently identified the molecular basis for the mitochondrial Ca2+ uniporter (MCU), the main pathway for Ca2+ entry into mitochondria. We developed new, myocardial-selective transgenic and inducible knock out mouse models of MCU inhibition to test this concept in vivo. Our new mice with myocardial MCU inhibition are viable and our preliminary data show they are resistant to myocardial death after isoproterenol infusion. Here we propose to establish how MCU inhibition contributes to myocardial physiology and disease. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) contributes to heart failure by promoting defective intracellular Ca2+ handling, including mitochondrial Ca2+ overload, but the molecular targets for cardiomyopathic actions of CaMKII are uncertain. During the original period of this competing renewal, we found that CaMKII is present in mitochondria, that mitochondrial CaMKII inhibition reduces MCU- mediated mitochondrial Ca2+ entry and protects against mitochondrial Ca2+ overload in clinically-relevant models of heart failure (Joiner Nature 2012). We identified key sites on MCU (serines 57 and 92) that are essential for CaMKII agonist actions. Thus, MCU is the first validated CaMKII target protein in mitochondria. Here we propose to test the role of mitochondrial CaMKII at MCU in myocardial physiology and disease. The overall goal of this competitive renewal application is to determine the importance of MCU and mitochondrial CaMKII-dependent MCU phosphorylation for myocardial metabolism and disease using 3 specific aims. 1. Determine the effect of MCU inhibition on myocardial physiology; 2. Determine the effect of MCU inhibition on myocardial responses to pathological stress; 3. Determine the effects of CaMKII-dependent MCU phosphorylation on metabolism and disease.

描述（由申请人提供）：心力衰竭是一个重大的公共卫生问题，没有足够的治疗方法。心肌 Ca2+ 稳态丧失和线粒体 Ca2+ 过载是导致心力衰竭进展的基本事件，但目前没有可用的治疗方法可以阻止线粒体 Ca2+ 过量进入。 2011年，经过50年的研究，两个小组独立确定了线粒体Ca2+单向转运蛋白（MCU）的分子基础，MCU是Ca2+进入线粒体的主要途径。我们开发了新的、心肌选择性转基因和可诱导敲除 MCU 抑制的小鼠模型，以在体内测试这一概念。我们的抑制心肌 MCU 的新小鼠是可行的，我们的初步数据显示它们在输注异丙肾上腺素后能够抵抗心肌死亡。在这里，我们建议确定 MCU 抑制如何影响心肌生理学和疾病。多功能 Ca2+ 和钙调蛋白依赖性蛋白激酶 II (CaMKII) 通过促进细胞内 Ca2+ 处理缺陷（包括线粒体 Ca2+ 超载）而导致心力衰竭，但 CaMKII 心肌病作用的分子靶点尚不确定。在这种竞争更新的最初阶段，我们发现 CaMKII 存在于线粒体中，线粒体 CaMKII 抑制减少了 MCU 介导的线粒体 Ca2+ 进入，并防止临床相关心力衰竭模型中的线粒体 Ca2+ 过载 (Joiner Nature 2012)。我们确定了 MCU 上对 CaMKII 激动剂作用至关重要的关键位点（丝氨酸 57 和 92）。因此，MCU 是线粒体中第一个经过验证的 CaMKII 靶蛋白。在这里，我们建议测试 MCU 线粒体 CaMKII 在心肌生理学和疾病中的作用。这一竞争性更新应用的总体目标是通过 3 个具体目标确定 MCU 和线粒体 CaMKII 依赖性 MCU 磷酸化对心肌代谢和疾病的重要性。 1.确定MCU抑制对心肌生理的影响； 2.确定MCU抑制对心肌病理应激反应的影响； 3. 确定 CaMKII 依赖性 MCU 磷酸化对代谢和疾病的影响。