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：
8915239
负责人：
MARK E ANDERSON
金额：
$ 39.22万
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/8915239
关键词：
ATP Synthesis Pathway Agonist Automobile Driving Binding Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Calcium/calmodulin-dependent protein kinase Cardiac Myocytes Cardiomyopathies Cell Death Cessation of life Charge Data Disease Enzymes Event Figs - dietary Genes Goals Health Heart 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 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）：心力衰竭是没有足够疗法的主要公共卫生问题。心肌CA2+稳态和线粒体CA2+超负荷的丧失是驱动心力衰竭进展的基本事件，但目前没有可用的疗法阻止线粒体CA2+进入。 2011年，经过50年的搜索，两组独立地确定了线粒体Ca2+ Uniporter（MCU）的分子基础，这是Ca2+进入线粒体的主要途径。我们开发了新的，心肌选择性的转基因和诱导的MCU抑制小鼠模型，以在体内测试这一概念。我们具有心肌MCU抑制作用的新小鼠是可行的，我们的初步数据表明它们在输注异丙肾上腺素后对心肌死亡具有抗性。在这里，我们建议建立MCU抑制作用如何有助于心肌生理和疾病。多功能Ca2+和钙调蛋白依赖性蛋白激酶II（CAMKII）通过促进缺陷的细胞内Ca2+处理，包括线粒体Ca2+过载，导致心力衰竭，但尚不确定CAMKII的心肌病作用的分子靶标。在这种竞争更新的最初时期，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，并防止了线粒体CA2+线粒体CA2+临床失败模型中的心脏失败模型（Jober Anture Anture 2012）。我们确定了MCU（丝绸57和92）上的关键站点，这些位点对于Camkii激动剂作用至关重要。因此，MCU是线粒体中第一个经过验证的CAMKII靶蛋白。在这里，我们建议测试线粒体CAMKII在MCU在心肌生理和疾病中的作用。这种竞争性更新应用的总体目标是确定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抑制对心肌反应对病理压力的影响； 3。确定CAMKII依赖性MCU磷酸化对代谢和疾病的影响。