Role of EHD proteins in cardiac excitability and disease

描述（由申请人提供）：心脏的收缩依赖于心肌细胞中完整膜蛋白的适当表达、运输和保留。这些蛋白质从离子通道和转运蛋白到激素受体不等。所有这些都在控制心脏收缩以及对生理和病理生理刺激的短期和长期适应中发挥关键作用。表达的蛋白质的谱是动态的，并且其被调节以确保对应激的适当响应。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出了这一点。然而，尽管其明显的重要性，很少有人知道，甚至身份（或功能）的细胞内分子通路的运输和靶向的内在膜蛋白的背景下，天然心脏。该研究项目的重点是确定膜蛋白靶向和调节心脏的新途径，目的是确定调节心脏膜兴奋性的新机制。含Eps 15同源结构域（EHD）基因产物（EHD 1 -4）是细胞内蛋白，其似乎是内体运输、脂质稳态、膜蛋白再循环和运输的关键调节剂。以前在心脏中没有特征，最近的证据表明，这种蛋白质家族可能在心肌中的蛋白质运输中起着不可或缺的作用。值得注意的是，我们的小组最近发现了这些蛋白质之一EHD 3在心脏Na/Ca交换器（NCX）的膜运输中的重要作用。该提案的目标是使用EHD蛋白缺乏的尖端体内模型直接测试这些蛋白在心脏结构和电活动中的作用。研究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蛋白在基线和长期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个表征功能分子机制的基础上的蛋白质运输和电重塑的心脏。 公共卫生相关性：该建议将定义Eps 15同源结构域（EHD）蛋白在心力衰竭和肥大期间心脏电重构中的作用。EHD蛋白是最近才在心脏中发现的一个新的蛋白质家族，我们的初步发现阐明了这些蛋白质在膜蛋白靶向和调节中的关键作用。该蛋白质家族可能作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.