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".
It is estimated that five million Americans have heart failure, a syndrome with 5-year mortality of 50%. Often, early events in heart failure pathogenesis center around dysregulation of Ca2+ handling. Here, we propose to elucidate the role of a recently discovered protein which may serve as a master regulator of Ca2+ homeostasis in both physiology and disease.
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