Defining New Pathways for Complex Human Heart Failure and Arrhythmia

定义复杂人类心力衰竭和心律失常的新途径

基本信息

批准号：
10617851
负责人：
Elisa Ann Bradley
金额：
$ 16.09万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617851
关键词：
ANK2 gene ANK3 gene Actins Adult Affect Ankyrins Area Arrhythmia Biology Cardiac Cardiomyopathies Cardiovascular Diseases Cardiovascular system Caring Cells Child Clinical Communities Complex Congenital Cardiovascular Abnormality Cytoskeleton Data Defect Diagnostic Dilated Cardiomyopathy Disease Elements Etiology Evaluation Exhibits Functional disorder Genes Goals Heart Heart Block Heart Diseases Heart failure Heritability Human In Vitro Intercalated disc Investigation Ion Channel Left ventricular structure Link Membrane Membrane Proteins Mentors Modeling Molecular Morphology Mus Muscle Cells Mutation Myocardial Contraction Myocardial dysfunction Myocardium Neurons Pathologic Pathway interactions Patients Persons Phenotype Physicians Physiological Play Population Post-Translational Protein Processing Protein Isoforms Proteins Regulation Risk Assessment Role Scientist Signal Transduction Sodium Channel Spectrin Stimulus Structure Testing Thinness Tissues Variant Ventricular Arrhythmia Work betaIV spectrin career congenital heart disorder disease natural history disease phenotype gene product heart function human disease improved in vivo insight loss of function loss of function mutation novel recruit response sudden cardiac death training opportunity voltage

项目摘要

Project Summary Normal cardiac function requires synchronization of structural and electrical molecules within the heart. Defects affecting cardiac excitability linked to sudden cardiac death affect ½ million people, and those affecting contractile function, such as in the case of cardiomyopathy, impact another 5.7 million patients in the U.S. each year. However, often overlooked are cardiovascular (CV) phenotypes that result in both electrical and contractile dysfunction. This relationship between contractile and electrical elements is critically important to understand in the patient with congenital heart disease (CHD). There are now more adults (ACHD) living with CHD than children, and in this population the most common late manifestation of CHD is a severely complex phenotype hallmarked by both heart failure and arrhythmia. The ACHD community recognizes the importance of each of these entities, and has set forth high-priority areas of study surrounding heart failure and arrhythmia, with the goal of using models aimed at the ‘cellular keystones underlying CHD’. This proposal embraces that focus, shifting from the study of each of these late CV sequela independently, and taking a broader look at the complex CHD phenotypes that result in both electrical and contractile dysfunction. We have identified a molecule which we believe has both CV electrical and contractile consequences, thereby serving as a good foundational model to study complex phenotypes resulting in combination arrhythmia and heart failure. Ankyrins are a membrane- associated protein directly linked with targeting ion channels in myocytes, neurons and other excitable cells. In heart, ankyrins-B and –G, which function to support myocyte actin/spectrin in the cytoskeleton and function in cellular organization, transport, gating and post-translational modification, are associated with critical membrane ion channels. Canonical AnkG is required for normal NaV1.5 channel targeting in the heart. However, we have identified a novel ‘giant’ cardiac ankyrin-G isoform that we implicate is critical for normal cardiac structure, contractility and electrical conduction. Mice lacking ‘Giant AnkG’ display a dilated and thinned left ventricle with reduced systolic function, consistent with a dilated cardiomyopathy phenotype. These same mice also exhibit electrical dysfunction including ventricular arrhythmia and high-degree heart block. Our new preliminary data support our central hypothesis: A single ankyrin gene produces two separate molecules- each with unique roles in cardiac structural and electrical function. We hypothesize that novel cardiac Giant AnkG functions via a unique sodium-channel independent mechanism leading to regulation myocyte structure, membrane organization and abnormal intra- and inter-cellular signaling. Ultimately, loss of function of this large gene product leads to altered myocardial contraction and defective electrical function.

项目摘要正常的心脏功能需要在心脏内的结构和电分子同步。影响与心脏突然死亡有关的心脏兴奋的缺陷影响½万人，以及影响的患者收缩功能，例如心肌病，影响美国另外570万患者年。但是，经常被忽视的是心血管（CV）表型，导致电气和收缩功能障碍。收缩和电气元素之间的这种关系至关重要先天性心脏病（CHD）的患者。现在，与CHD一起生活的成年人（ACHD）多于儿童，在这个人群中，最常见的冠心病晚期表现是一种严重复杂的表型以心力衰竭和心律不齐为标志。 ACHD社区认识到每个社区的重要性这些实体，并提出了围绕心力衰竭和心律不齐的高优先研究领域，使用针对“晶体冠心基础钥匙石”的模型的目标。该提议包含了重点，从对所有这些晚期CV续集的研究中转移，并更广泛地看一下复合物导致电气和收缩功能障碍的CHD表型。我们已经确定了一个分子我们认为具有简历电气和收缩后果，从而充当良好的基础模型研究复杂的表型，导致心律不齐和心力衰竭组合。 Ankyrins是膜 - 相关蛋白与肌细胞，神经元和其他令人兴奋的细胞中的靶向离子通道直接相关。在心脏，Ankyrins-b和–g，在细胞骨架中支持肌细胞肌动蛋白/光谱的功能细胞组织，运输，门控和翻译后修饰与关键膜有关离子通道。正常的NAV1.5通道靶向心脏中需要规范ANKG。但是，我们有确定了一种新型的“巨型”心氨基酸G亚型，我们暗示，对于正常心脏结构至关重要，收缩性和电导传导。缺乏“巨型ANKG”的小鼠展示了一个扩张而稀薄的左心室收缩功能降低，与扩张的心肌病表型一致。这些相同的小鼠也表现出电气功能障碍，包括心室心律失常和高度心脏障碍。我们的新初步数据支持我们的中心假设：一个单氨基蛋白基因产生两个独立的分子 - 每个分子具有独特的作用在心脏结构和电气功能中。我们假设那个新颖的心脏巨人ANKG通过独特的功能钠通道独立的机制导致肌细胞结构，膜组织和异常细胞内信号传导。最终，这种大基因产物的功能丧失会导致改变心肌收缩和电功能有缺陷。