Defining New Pathways for Complex Human Heart Failure and Arrhythmia

项目摘要 正常的心脏功能需要心脏内部结构和电子分子的同步。 与心脏性猝死相关的影响心脏兴奋性的缺陷影响着50万人，而那些影响 收缩功能，例如心肌病，在美国影响着另外570万患者 年。然而，经常被忽视的是导致电和收缩的心血管(CV)表型 功能障碍。了解收缩和电学元素之间的这种关系至关重要 先天性心脏病(CHD)患者。现在有更多的成年人(ACHD)患有CHD 儿童，在这个人群中，CHD最常见的晚期表现是一种极其复杂的表型 以心力衰竭和心律失常为特征。ACHD社区认识到每一个 这些实体，并提出了围绕心力衰竭和心律失常的高度优先研究领域， 我们的目标是使用针对“CHD背后的细胞基石”的模型。这项提案包含了这一重点， 从对这些晚期心血管后遗症的研究转向独立的，并更广泛地看待复杂的 导致电和收缩功能障碍的CHD表型。我们已经确定了一种分子 我们认为，它同时具有CV、电学和收缩效应，因此可以作为一个很好的基础模型 研究导致心律失常和心力衰竭的复杂表型。Ankyrins是一种膜- 相关蛋白直接与心肌细胞、神经元和其他可兴奋细胞中的靶向离子通道相连。在……里面 心脏，Ankyrins-B和-G，它们的功能是支持细胞骨架中的肌细胞肌动蛋白/幽灵蛋白，并在 细胞组织、运输、门控和翻译后修饰与关键膜有关 离子通道。在心脏中正常的NAV1.5频道靶向需要标准的AnkG。然而，我们有 发现了一种新的巨大的心脏Ankyrin-G亚型，我们认为它对正常的心脏结构至关重要， 伸缩性和导电性。缺乏‘Giant AnkG’的小鼠表现为左心室扩张变薄 收缩功能降低，符合扩张型心肌病的表型。同样是这些老鼠也展示了 电功能障碍包括室性心律失常和高度心脏传导阻滞。我们新的初步数据 支持我们的中心假设：单个锚蛋白基因产生两个独立的分子--每个分子都有独特的作用 在心脏结构和电功能方面。我们假设新的心脏巨人AnkG通过一种独特的 钠通道非依赖机制导致调节心肌细胞结构、膜组织和 细胞内和细胞间信号异常。最终，这种大基因产物的功能丧失会导致改变 心肌收缩和电功能缺陷。

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.