Defining New Pathways in Heart Failure and Arrhythmia

定义心力衰竭和心律失常的新途径

• 批准号: 9224042
• 负责人: Sakima Ahmad Smith
• 金额: $ 14.97万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224042
• 关键词: Actins; Age-Years; Animal Model; Arrhythmia; Calcium; Cardiac; Cell Nucleus; Cell membrane; Cells; Cellular biology; Chronic stress; Coupling; Critical Pathways; Cytoskeletal Proteins; Cytoskeleton; Data; Defect; Development; Diagnostic; Dilated Cardiomyopathy; Disease; Epidemic; Functional disorder; Genes; Genetic Transcription; Genotype; Goals; Health; Heart; Heart failure; Human; Ion Channel; Knowledge; Left; Link; Mechanics; Medical; Medical Genetics; Membrane; Membrane Proteins; Microtubules; Modeling; Molecular; Mus; Muscle Cells; Muscular Dystrophies; Mutation; Myocardial; Myopathy; Network-based; Pathology; Pathway interactions; Patients; Phenotype; Play; Post-Translational Protein Processing; Proteins; Regulation; Regulatory Pathway; Research Infrastructure; Role; Signal Transduction; Spectrin; Structure; Testing; Translating; Variant; Ventricular; Woman; Work; acute stress; arrhythmogenic cardiomyopathy; base; cardiac resynchronization therapy; cohort; disease diagnosis; genetic regulatory protein; improved; in vivo; innovation; innovative technologies; left ventricular assist device; lifetime risk; loss of function; loss of function mutation; men; mortality; mouse model; programs; transmission process

Project Summary Dilated cardiomyopathies, heart failure (HF), and arrhythmias are a significant health burden. Despite the improving medical therapies, cardiac resynchronization therapies, and left ventricular assist devices, HF remains a global epidemic. The lifetime risk of developing HF is 20% with a 5 year age-adjusted mortality at 59% and 45% for men and women, respectively. Thus, the identification of pathways underlying development and progression of HF and arrhythmias is essential for the creation of improved diagnostics and treatments. Over the past two decades, the cardiac cytoskeleton has emerged as a central governing factor in the control of cardiac membrane integrity, and dysfunction in cytoskeleton and cytoskeletal-associated proteins has been directly linked with a host of human cardiac pathologies, most notably cardiac myopathies and dystrophies. In fact, human loss-of-function variants in cardiac cytoskeletal or cytoskeletal-associated genes that alter myocyte signal transduction, myocardial mechanics, and force transmission are now directly linked with dilated cardiomyopathy, muscular dystrophy, and arrhythmogenic cardiomyopathy. In contrast to myopathy and dystrophy fields, the role of the cytoskeleton in normal electrical function is not well resolved. Further, until only recently, human arrhythmia mechanisms were limited to mutations in ion channels. However, our group and now others have defined a second class of arrhythmias due to mutations in channel-associated proteins. Dysfunction in these proteins is linked with diverse pathologies including defects in channel synthesis and targeting, gating, and post-translational modifications. While this information has been important for new disease diagnosis and fundamental cardiac cell biology, there remain large cohorts of phenotype positive/genotype negative patients with familial forms of HF and arrhythmia. Further, there remain large knowledge gaps regarding the pathways underlying more common forms of acquired HF and arrhythmia. The overall goal of my program is to define new cell and molecular pathways underlying HF and arrhythmia. Based on clinical and genetic findings, we uncovered a new and essential cytoskeletal-based pathway critical for cardiac electrical function. Our preliminary data, that spans human to molecule, utilizes new in vivo mouse models and targeting strategies and innovative technologies supports our central hypothesis that the cytoskeletal protein II spectrin serves as an unexpected and integral regulatory node for the organization of critical myocyte membrane and membrane-associated proteins. Further, our data support that dysfunction in this pathway is an underlying factor for cardiac electrical and structural remodeling in HF and arrhythmia. Our proposal will test the new roles of the II spectrin pathway in HF and arrhythmia as well as the molecular mechanisms underlying II spectrin regulation in disease: We will 1) Define the in vivo role of II spectrin in heart failure; 2) Define the cell and molecular roles of II spectrin in heart failure; 3) Define new in vivo molecular mechanisms underlying cardiac II spectrin regulation.

项目摘要 扩张性心肌病、心力衰竭（HF）和心律失常是显著的健康负担。尽管 改进的药物治疗、心脏起搏治疗和左心室辅助装置、HF 仍然是一种全球流行病。发生HF的终生风险为20%，5岁校正死亡率为 男性和女性分别为59%和45%。因此，确定发展的基本途径 HF和心律不齐的进展对于改进诊断和治疗是必不可少的。 在过去的二十年里，心脏细胞骨架已经成为控制心肌缺血的一个中心控制因素。 心脏膜完整性的损害，以及细胞骨架和细胞骨架相关蛋白的功能障碍， 与许多人类心脏病直接相关，最显著的是心肌病和营养不良。在 事实上，人类心脏细胞骨架或细胞骨架相关基因的功能丧失变异， 信号传导、心肌力学和力的传递现在与扩张的 心肌病、肌肉萎缩症和致心律失常性心肌病。 与肌病和营养不良领域相反，细胞骨架在正常电功能中的作用是 没有很好的解决。此外，直到最近，人类心律失常机制仅限于离子突变。 渠道然而，我们的小组和现在其他人已经定义了第二类心律失常， 通道相关蛋白。这些蛋白质的功能障碍与包括缺陷在内的多种病理学有关 在通道合成和靶向、门控和翻译后修饰中。虽然这些信息 对于新的疾病诊断和基础心脏细胞生物学很重要，仍然有大量的 表型阳性/基因型阴性的家族性HF和心律失常患者。此外，还有 关于获得性HF和心律失常的更常见形式的潜在途径的巨大知识差距。 我的计划的总体目标是确定新的细胞和分子途径的基础HF和心律失常。 基于临床和遗传学的发现，我们发现了一个新的和必要的细胞内途径 对心脏电功能至关重要我们的初步数据，跨越人类分子，利用新的体内 小鼠模型、靶向策略和创新技术支持了我们的中心假设， 细胞骨架蛋白GSTII血影蛋白作为一个意想不到的和完整的调节节点的组织， 关键的肌细胞膜和膜相关蛋白。此外，我们的数据支持， 该通路是HF和心律失常中心脏电和结构重塑的潜在因素。我们 该提案将测试HF II血影蛋白通路在HF和心律失常中的新作用，以及 在疾病中，潜在的β-II血影蛋白调节机制：我们将1）定义β-II血影蛋白在疾病中的体内作用， 心力衰竭; 2）定义心力衰竭中的细胞和分子作用; 3）定义新的体内 心肌细胞膜蛋白II调节的分子机制。