STIM1: Master Regulator of Calcium Homeostasis in Cardiomyocytes

描述（由申请人提供）：应激诱导的心肌肥大生长是许多心脏病（包括心力衰竭）发病机制中不可或缺的一步。虽然涉及多个信号通路，但普遍认为细胞内Ca 2+稳态的改变是一个近端事件。事实上，异常的细胞内Ca 2+稳态是病理性心脏重塑的中心触发因素。基质相互作用分子1（stromal interaction molecule 1，STIM 1）是一种钙离子传感蛋白，其功能是测量细胞内钙储存。在非兴奋性细胞中，当Ca 2+储存耗尽时，STIM 1易位到质膜近端的结构域以激活介导Ca 2+内流的通道（储存操作的Ca 2+内流，SOCE）。因此，STIM 1控制Ca 2+储存的补充，这是细胞稳态所需的过程。现在，最近的证据已经揭示了STIM 1和SOCE在心脏中的作用。然而，关于STIM 1依赖性SOCE在心脏中的机制和/或其在应激反应中的作用知之甚少。我们已经进行了初步的研究，支持这一假设，STIM 1介导的SOCE中起着核心作用的异常Ca 2+稳态，触发心脏肥大。在这里，我们建议定义机制STIM 1与SOCE连接，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STIM 1剪接异构体，其中之一是由肥大应激。这些新的蛋白质的功能是未知的，我们建议定义它们（目标2）。除此之外，我们和其他人有证据表明STIM 1在控制Ca 2+进入的非SOCE机制中发挥作用，包括我们提议定义的L型Ca 2+通道（目标3）。两者合计，最近的观察表明，STIM 1是一个主调节器的Ca 2+处理和稳态在兴奋性和非兴奋性细胞。 我们建议探讨STIM 1，STIM 1依赖的SOCE，STIM 1依赖的LTCC的相互控制，在心脏重塑中的作用，并确定潜在的机制。在此过程中，我们将阐明病理性心脏生长，重塑和Ca 2+稳态的新机制。可以想象，Ca 2+处理的特定机制的治疗滴定将作为预防、减缓甚至逆转心力衰竭的策略出现。因此，我们期望这些见解有一天可能会导致临床相关性的进步。此外，受益将增加到其他领域，如离子通道生物物理学，和其他器官系统，其中STIM 1，SOCE和L型通道是普遍的（例如，一系列广泛的可兴奋和不可兴奋的细胞）。总之，这些研究对于NIH“保护和改善健康”的使命具有重要意义和高度相关性。

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".