STIM1: Master Regulator of Calcium Homeostasis in Cardiomyocytes

STIM1：心肌细胞钙稳态的主调节器

• 批准号: 8722622
• 负责人: JOSEPH A HILL
• 金额: $ 38.96万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-18 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722622
• 关键词: Adult; Agonist; Agreement; American; Area; Biophysics; Calcium; Cardiac; Cardiac Myocytes; Cell membrane; Cells; Chest; Clinical; Coupled; Databases; Disease; Endoplasmic Reticulum; Event; Expressed Sequence Tags; Genes; Growth; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Homeostasis; Image; Ion Channel; Lead; Link; Mediating; Mind; Mission; Molecular; Myocardium; Neonatal; Pathogenesis; Physiology; Play; Post-Translational Protein Processing; Process; Protein Isoforms; Proteins; RNA Splicing; Regulation; Relative (related person); Reporting; Rest; Reverse Transcriptase Polymerase Chain Reaction; Role; Sarcoplasmic Reticulum; Signal Pathway; Signal Transduction; Stress; Syndrome; Therapeutic; Titrations; United States National Institutes of Health; Variant; body system; cell type; clinically relevant; constriction; expectation; fetal; human STIM1 protein; improved; in vivo; insight; loss of function; mortality; novel; patch clamp; pressure; prevent; programs; protein function; public health relevance; receptor; research study; response; sensor; skeletal; voltage

DESCRIPTION (provided by applicant): Stress-induced hypertrophic growth of the myocardium is an integral step in the pathogenesis of many forms of heart disease, including heart failure. Although multiple signaling pathways are involved, there is general agreement that altered intracellular Ca2+ homeostasis is a proximal event. Indeed, abnormal intracellular Ca2+ homeostasis is a central trigger of pathological cardiac remodeling. STIM1 (stromal interaction molecule 1), a Ca2+ sensor protein, functions to gauge intracellular Ca2+ stores. In nonexcitable cells, when Ca2+ stores are depleted, STIM1 translocates to a domain proximal to the plasma membrane to activate channels the mediate Ca2+ influx (store-operated Ca2+ entry, SOCE). Thus, STIM1 governs the repletion of Ca2+ stores, a process required for cellular homeostasis. Now, recent evidence has uncovered a role for STIM1 and SOCE in heart. Yet, little is known regarding mechanisms of STIM1-dependent SOCE in heart and/or its role in stress responsiveness. We have performed preliminary studies that support the hypothesis that STIM1-mediated SOCE plays a central role in the abnormal Ca2+ homeostasis that triggers cardiac hypertrophy. Here, we propose to define mechanisms linking STIM1 with SOCE and elucidate the role of this axis in pathological cardiac remodeling (Aim 1). We have identified novel STIM1 splicing isoforms, one of which is regulated by hypertrophic stress. The functions of these novel proteins are unknown, and we propose to define them (Aim 2). Beyond that, we and others have evidence pointing to a role for STIM1 in governing non-SOCE mechanisms of Ca2+ entry, including the L-type Ca2+ channel, which we propose to define (Aim 3). Taken together, recent observations suggest that STIM1 is a master regulator of Ca2+ handling and homeostasis in both excitable and nonexcitable cells. We propose to explore the role of STIM1, STIM1-dependent SOCE, and STIM1-dependent reciprocal control of LTCC, in cardiac remodeling and define underlying mechanisms. In so doing, we will elucidate novel mechanisms of pathological cardiac growth, remodeling, and Ca2+ homeostasis. It is conceivable that therapeutic titration of specific mechanisms of Ca2+ handling will emerge as a strategy to prevent, slow, or even reverse, heart failure. Thus, it is our expectation that these insights may lead, one day, to advances with clinical relevance. In addition, benefit will accrue to other areas such as ion channel biophysics, and other organ systems where STIM1, SOCE, and L-type channels are prevalent (e.g. a wide array of excitable and nonexcitable cells). Together, these studies are significant and highly relevant to the NIH mission to "protect and improve health".

描述（由申请人提供）：压力诱导的心肌肥厚生长是多种心脏病（包括心力衰竭）发病机制中不可或缺的一步。尽管涉及多种信号通路，但普遍认为细胞内Ca2+稳态的改变是近端事件。事实上，异常的细胞内Ca2+稳态是病理性心脏重构的中心触发因素。STIM1（基质相互作用分子1）是一种Ca2+传感器蛋白，具有测量细胞内Ca2+储存的功能。在不可兴奋的细胞中，当Ca2+储存耗尽时，STIM1易位到质膜近端区域，激活介导Ca2+内流的通道（储存操作的Ca2+进入，SOCE）。因此，STIM1控制Ca2+储存的补充，这是细胞稳态所需的一个过程。现在，最近的证据揭示了STIM1和SOCE在心脏中的作用。然而，关于心脏中stim1依赖性SOCE的机制和/或其在应激反应中的作用，我们知之甚少。我们已经进行了初步研究，支持stim1介导的SOCE在触发心肌肥厚的异常Ca2+稳态中起核心作用的假设。在这里，我们提出定义连接STIM1和SOCE的机制，并阐明该轴在病理性心脏重塑中的作用（目的1）。我们已经确定了新的STIM1剪接异构体，其中一个受肥厚应激调节。这些新蛋白的功能是未知的，我们建议对它们进行定义（目的2）。除此之外，我们和其他人有证据表明STIM1在控制Ca2+进入的非soce机制中的作用，包括我们建议定义的l型Ca2+通道（Aim 3）。综上所述，最近的观察表明，STIM1是可兴奋和不可兴奋细胞中Ca2+处理和稳态的主要调节剂。我们建议探讨STIM1、STIM1依赖性SOCE和STIM1依赖性LTCC的相互控制在心脏重塑中的作用，并确定其潜在机制。在此过程中，我们将阐明病理性心脏生长、重塑和Ca2+稳态的新机制。可以想象，Ca2+处理的特定机制的治疗滴定将成为一种预防、减缓甚至逆转心力衰竭的策略。因此，我们期望有一天，这些见解可能会导致与临床相关的进展。此外，离子通道生物物理学以及STIM1、SOCE和l型通道普遍存在的其他器官系统（例如，大量可兴奋和不可兴奋的细胞）等其他领域也将受益。总之，这些研究意义重大，与NIH“保护和改善健康”的使命高度相关。