Defining New Pathways in Heart Failure and Arrhythmia

项目摘要 扩张型心肌病、心力衰竭(HF)和心律失常是严重的健康负担。尽管 不断改进的药物治疗、心脏再同步治疗和左心辅助装置 仍然是一种全球流行病。发生心力衰竭的终生风险为20%，年龄调整后的5年死亡率为 男性和女性分别为59%和45%。因此，确定发展的根本途径 心力衰竭和心律失常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，心肌细胞骨架已经成为控制心脏功能的中心控制因素。 细胞膜的完整性，以及细胞骨架和细胞骨架相关蛋白的功能障碍 与一系列人类心脏疾病直接相关，最明显的是心脏肌病和营养不良。在……里面 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会改变心肌细胞 信号转导、心肌力学和力传递现在直接与扩张型 心肌病、肌营养不良症和致心律失常性心肌病。 与肌病和营养不良领域不同，细胞骨架在正常电功能中的作用是 没有得到很好的解决。此外，直到最近，人类心律失常的机制还仅限于离子突变。 频道。然而，我们的团队和现在的其他团队已经定义了第二类心律失常，这是由于 通道相关蛋白。这些蛋白的功能障碍与包括缺陷在内的多种病理因素有关。 在通道合成和定位、门控和翻译后修改方面。虽然这一信息具有 对于新的疾病诊断和基础心肌细胞生物学来说是重要的，仍然有大量的 有家族性心衰和心律失常的表型阳性/基因阴性患者。此外，还有 关于更常见形式的获得性心衰和心律失常的潜在途径，知识差距很大。 我这个项目的总体目标是定义新的细胞和分子通路，这些通路是心衰和心律失常的基础。 基于临床和遗传学研究结果，我们发现了一种新的、基于细胞骨架的重要途径。 对心脏电功能至关重要。我们的初步数据，从人到分子，利用了体内的新技术 老鼠模型、靶向策略和创新技术支持我们的中心假设 细胞骨架蛋白II是一个意想不到的完整的调节节点，对组织 关键的心肌细胞膜和膜相关蛋白。此外，我们的数据支持这种功能障碍 这一途径是心力衰竭和心律失常心脏电重构和结构重构的潜在因素。我们的 该提案将测试II血影蛋白通路在心力衰竭和心律失常中的新作用以及分子 疾病中II血影蛋白调控的机制：我们将1)确定II血影蛋白在体内的作用 心力衰竭；2)确定II血影蛋白在心力衰竭中的细胞和分子作用；3)在体内定义新的 心脏II血影蛋白调控的分子机制。

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.