CaMKII signaling in physiology, heart failure and arrhythmias

生理学、心力衰竭和心律失常中的 CaMKII 信号传导

基本信息

批准号：
10077577
负责人：
MARK E ANDERSON
金额：
$ 119.86万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-22 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077577
关键词：
Animal Model Arrhythmia Asthma Award Biology Brain-Derived Neurotrophic Factor CRISPR/Cas technology Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Cardiovascular Diseases Cells Complex Computer Models Data Dilated Cardiomyopathy Disease Drosophila genus Drosophila melanogaster Goals Health Heart Heart failure Injury Knowledge Longevity Metabolic Metabolism Mitochondria Modeling Molecular Mus Nature Organelles Outcome Oxidants Oxidative Stress Paraquat Pathologic Pathway interactions Phenotype Physiological Physiology Production Protein Isoforms Public Health Reactive Oxygen Species Research Research Personnel Resistance Role Sepsis Signal Transduction Skeletal Muscle Testing Thinness Weight Gain antioxidant therapy exercise capacity fighting fly imaging study improved innovation insight insulin sensitivity metabolic abnormality assessment mortality myocardial injury oxidant stress oxidation phosphoproteomics prevent programs response

项目摘要

Abstract Heart failure and arrhythmias occur together, are marked by increased reactive oxygen species (ROS), and are major, unsolved public health problems. Despite this, ROS can be beneficial. However, clear molecular mechanisms supporting the benefits of ROS are lacking. The potential for ROS to be ‘good and bad’ is called the ROS paradox. This Outstanding Investigator Award application will propose innovative approaches to understanding and dissecting healthy from pathological ROS. The goal of this research program is to test a disruptive concept that ROS activation of the multifunctional calcium and calmodulin kinase II (CaMKII) by isoform and organelle selective pathways determine physiological and pathological outcomes of ROS signaling. We discovered that oxidation activates CaMKII (ox-CaMKII, Erickson Cell 2008) and established that ox-CaMKII, the major CaMKII isoform in heart, causes heart failure and arrhythmias. Our newest studies extended these findings to show that ox-CaMKII also contributes to asthma. In sharp contrast, our new preliminary data indicate that ox-CaMKII, an isoform enriched in skeletal muscle, is beneficial and enhances endurance, insulin sensitivity, lean phenotype, PGC-1, and expression or brain derived neurotrophic factor (BDNF), a myokine that improves exercise capacity and protects against myocardial injury. Our group discovered that CaMKII is present in mitochondria and that mitochondrial-targeted inhibition of CaMKII protects against common forms of myocardial injury associated with high ROS (Joiner Nature 2012). Here we propose to pursue new models of global (i.e. body-wide) mitochondrial CaMKII inhibition in flies (Drosophila melanogaster) and mice developed for the proposed OIA studies. Mitochondrial CaMKII inhibited flies have a prolonged lifespan and resistance to paraquat induced oxidant injury, while mice with global CaMKII inhibition have reduced mortality in sepsis and increased weight gain. We performed new phosphoproteomic and metabolic analyses that identified unanticipated mitochondrial CaMKII targets with central roles in metabolism and ROS production. Our preliminary computational modeling and experimental data suggest that physiological activation of mitochondrial CaMKII contributes to a beneficial metabolic fight or flight response that increases ATP; however, sustained and excessive mitochondrial CaMKII activity causes dilated cardiomyopathy due to loss of complex 1 and ATP deficiency. We and our collaborators will use state of the art computer modeling, imaging and metabolic studies, and generate a panel of mouse and Drosophila models using CRISPR/Cas9 to dissect contributions of CaMKII to specific targets relevant to heart failure, arrhythmias and to health. This research program requires an R35, or similar, mechanism because of its highly innovative concept that challenges current paradigms in CaMKII and ROS biology, the need to manage large amounts of data and generate new animals models, and the requirement for a prolonged timeframe.

抽象的心力衰竭和心律失常同时发生，其特征是活性氧 (ROS) 增加，并且尽管如此，ROS 仍然是一个尚未解决的重大公共卫生问题。缺乏支持 ROS 益处的机制 ROS 的潜力被称为“好与坏”。该杰出研究者奖申请将提出创新方法来解决 ROS 悖论。了解并剖析健康与病理 ROS 本研究项目的目标是测试 ROS 激活多功能钙和钙调蛋白激酶 II (CaMKII) 的颠覆性概念亚型和细胞器选择性途径决定 ROS 的生理和病理结果我们发现氧化会激活 CaMKII（ox-CaMKII，Erickson Cell 2008）并建立。我们最新的研究表明，ox-CaMKII（心脏中主要的 CaMKII 亚型）会导致心力衰竭和心律失常。扩展这些发现表明 ox-CaMKII 也会导致哮喘，与此形成鲜明对比的是，我们的新研究。初步数据表明，ox-CaMKII（一种富含骨骼肌的异构体）有益并增强耐力、胰岛素敏感性、瘦表型、PGC-1α 和脑源性神经营养因子的表达（BDNF），一种提高运动能力并防止心肌损伤的肌因子。发现 CaMKII 存在于线粒体中，并且线粒体靶向抑制 CaMKII 可保护对抗与高 ROS 相关的常见心肌损伤（Joiner Nature 2012）。追求果蝇全局（即全身）线粒体 CaMKII 抑制的新模型（果蝇黑腹果蝇）和为拟议的 OIA 研究而开发的小鼠，线粒体 CaMKII 抑制果蝇。延长寿命并抵抗百草枯诱导的氧化损伤，而全面抑制 CaMKII 的小鼠我们进行了新的磷酸化蛋白质组学研究，降低了败血症的死亡率并增加了体重。代谢分析发现了意想不到的线粒体 CaMKII 靶点在代谢中的核心作用我们的初步计算模型和实验数据表明：线粒体 CaMKII 的生理激活有助于有益的代谢战斗或逃跑反应增加 ATP；然而，持续且过度的线粒体 CaMKII 活性会导致扩张由于复合物 1 丢失和 ATP 缺乏而导致的心肌病我们和我们的合作者将使用该状态。艺术计算机建模、成像和代谢研究，并生成一组小鼠和果蝇模型使用 CRISPR/Cas9 剖析 CaMKII 对心力衰竭、心律失常相关特定靶标的贡献该研究项目需要 R35 或类似的机制，因为它具有高度创新性。挑战当前 CaMKII 和 ROS 生物学范式的概念，需要管理大量的数据并生成新的动物模型，以及延长时间的要求。