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

• 批准号: 10026490
• 负责人: MARK E ANDERSON
• 金额: $ 23.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/10026490
• 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

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 心力衰竭和心律不齐的同时出现，由活性氧（ROS）增加，并且 是主要的，未解决的公共卫生问题。尽管如此，ROS还是有益的。但是，透明分子 缺乏支持ROS益处的机制。 ROS成为“好与坏”的潜力称为 ROS悖论。该杰出的调查员颁发申请将提出创新的方法 从病理ROS中理解和剖析健康。该研究计划的目的是测试 破坏性的概念是ROS激活多功能钙和钙调蛋白激酶II（CAMKII） 同工型和Organelle选择性途径确定ROS的物理和病理结果 信号。我们发现氧化激活了Camkii（Ox-Camkii，Erickson Cell 2008），并建立了 牛卡米基（Ox-Camkii）是心脏中主要的CAMKII同工型，会导致心力衰竭和心律不齐。我们的最新研究 扩展了这些发现，以表明Ox-Camkii也有助于哮喘。相比之下，我们的新 初步数据表明，富含骨骼肌的同工型Ox-Camkii是有益的，并且增强了 耐力，胰岛素敏感性，瘦表型，PGC-1以及表达或脑衍生的神经营养因子 （BDNF），一种改善运动能力并预防心肌损伤的肌动物。我们的小组 发现Camkii存在于线粒体中，并且线粒体靶向CAMKII的抑制 反对与高ROS相关的心肌损伤的常见形式（Joiner Nature 2012）。我们在这里提出 购买新的全球（即全身）线粒体CAMKII抑制（果蝇）的新模型 Melanogaster）和小鼠为拟议的OIA研究而开发。线粒体camkii抑制蝇有一个 长时间的寿命和对帕拉quat诱导氧化物损伤的耐药性，而全球CAMKII抑制的小鼠 败血症的死亡率降低并增加体重增加。我们进行了新的磷蛋白质组学和 代谢分析鉴定出意外的线粒体CAMKII靶标具有中心作用在代谢中 和ROS生产。我们的初步计算建模和实验数据表明 线粒体CAMKII的生理激活有助于有益的代谢战斗或飞行反应 这增加了ATP；但是，持续并超过线粒体CAMKII活性会扩张 由于复合物1和ATP缺乏症的丧失，心肌病变。我们和我们的合作者将使用 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对与心力衰竭相关的特定目标的贡献 和健康。该研究计划需要R35或类似的机制，因为它具有高度创新性 挑战Camkii和Ros生物学中当前范式的概念，需要管理大量的概念 数据并生成新的动物模型，以及延长时间表的要求。