Role of EHD proteins in cardiac excitability and disease

描述(由申请人提供)：心脏的收缩依赖于完整的膜蛋白在心肌细胞中的正确表达、运输和保留。这些蛋白质从离子通道和转运体到激素受体都有不同。所有这些都在调节心脏收缩和对生理和病理生理刺激的短期和长期适应方面发挥关键作用。表达的蛋白质的图谱是动态的，它受到调节以确保对压力的适当反应。十年来将膜蛋白运输功能障碍与心脏病联系起来的研究突显了这一点。然而，尽管其明显的重要性，甚至对细胞内分子通路的身份(或功能)知道得很少，这些分子通路支撑着天然心脏中完整的膜蛋白的运输和靶向。本研究的重点是寻找新的心肌细胞膜蛋白靶向和调控途径，以明确心肌细胞膜兴奋性调控的新机制。EPS 15同源结构域(EHD)基因产物(EHD1-4)是细胞内蛋白质，似乎是内体转运、脂类内稳态、膜蛋白循环和转运的关键调节因子。最近的证据表明，该蛋白家族在心肌中的蛋白运输中可能起着不可或缺的作用。值得注意的是，我们的研究小组最近发现了其中一种蛋白EHD3在心脏膜钠钙交换(NCX)转运中的重要作用。这项建议的目的是利用EHD蛋白缺乏的活体模型直接测试这些蛋白在心脏结构和电活动中的作用。调查将在健康和衰竭的心脏中进行。本研究计划的目的是：1)确定EHD蛋白在基础状态和持续心脏应激期间对脊椎动物心脏功能的体内作用；2)确定EHD蛋白在维持心肌细胞兴奋性中的作用；3)确定EHD蛋白在细胞内蛋白运输中的作用。在这里完成的工作将是第一次表征支持蛋白质运输和心脏内电重构的功能分子机制。 公共卫生相关性：该提案将定义含有EPS 15同源结构域(EHD)的蛋白质在心力衰竭和肥厚期间心脏的电重构中所起的作用。EHD蛋白是最近在心脏中发现的一个新的蛋白质家族，我们的初步发现说明了这些蛋白质在膜蛋白靶向和调控中的关键作用。这个蛋白质家族可能成为对抗心力衰竭的新的治疗靶点。

DESCRIPTION (provided by applicant): Contraction of the heart relies upon the proper expression, trafficking, and retention of integral membrane proteins in cardiac muscle cells. These proteins vary from ion channels and transporters to hormone receptors. All play key roles in governing cardiac contraction and short and long term adaptations to physiological and pathophysiological stimuli. The profile of expressed proteins is dynamic, and it is regulated to assure the proper response to stress. This is highlighted by a decade of research linking dysfunction in membrane protein trafficking with heart disease. Yet, despite its obvious importance, little is known regarding even the identity (or the function) of the intracellular molecular pathways underpinning the trafficking and targeting of integral membrane proteins in the context of the native heart. The focus of this research program is to identify new pathways for membrane protein targeting and regulation in heart with the goal of defining novel mechanisms for the regulation of cardiac membrane excitability. Eps 15 homology domain-containing (EHD) gene products (EHD1-4) are intracellular proteins that appear to be key regulators of endosomal trafficking, lipid homeostasis, membrane protein recycling and trafficking. Previously uncharacterized in the heart, recent evidence demonstrated that this protein family likely plays indispensible roles in protein trafficking in cardiac muscle. Notably, n essential role for one of these proteins, EHD3, in the membrane trafficking of the Na/Ca exchanger (NCX) in heart was recently uncovered by our group. The goal of this proposal is to directly test the role of these proteins in cardiac structural and electrical activity using cuttin-edge in vivo models of EHD protein deficiency. Investigations will be conducted in both healthy and failing hearts. The aims of this research program are to 1) Define the in vivo roles of EHD proteins for vertebrate cardiac function at baseline and during prolonged cardiac stress, 2) identify the role of EHD proteins in the maintenance of myocyte excitability, and 3) define the role of EHD proteins in intracellular protein trafficking. The work completed here will be the firs to characterize the functional molecular mechanisms underpinning both protein trafficking and electrical remodeling within the heart. PUBLIC HEALTH RELEVANCE: This proposal will define the role that Eps 15 homology domain (EHD) containing proteins have in the electrical remodeling of the heart during heart failure and hypertrophy. EHD proteins are a new protein family only recently discovered in the heart, and our preliminary findings illustrate critical roles for these proteins in membrane protei targeting and regulation. This protein family may serve as novel therapeutic targets in the fight against heart failure.