Role of Orai in pathological cardiac remodeling

摘要 充血性心力衰竭（CHF）是美国的主要健康问题，影响约570万美国人。 随着一般人群的老龄化，CHF的发病率稳步增加。瑞士法郎的国家成本为 估计每年约307亿美元。虽然CHF的死亡率和经济影响很高， 其进展背后的详细分子机制仍未解决。了解 驱动心脏功能和结构恶化的基本过程对于开发新的 从根本上影响疾病进展的治疗。应激性心肌肥厚是一种 在许多形式的CHF的发病机制中的重要步骤，并且其抑制是治疗CHF的可行靶点。 干预基质相互作用分子1和2（STIM 1、STIM 2）及其分子伴侣奥赖蛋白 （Orai 1、Orai 2和Orai 3）构成了钙库操纵的钙通道（SOCC），并作为新的潜力浮出水面 针对病理性心脏肥大的治疗目标。我们发表的工作结果提供了强有力的 证据表明，STIM 1形成Ca 2+微区，通过改变心肌细胞的信号传导来控制心脏生长。 细胞骨架和促肥大基因程序。然而，奥赖对失败进展的贡献 心是未知的。我们已经产生了心脏特异性Orai 1和Orai 3敲除小鼠，并发现Orai 1 Orai 3与Ca ~（2+）/钙调素通路相关，而Orai 3与PI 3 K/AKT通路相关。我们 假设Orai 1-和Orai 3-依赖性Ca 2+信号传导是不同的，但共同协调心脏 肥大反应心脏Ca 2+和氧化应激的失调在CHF中似乎是共生的， 这一假设的推论是选择性抑制奥赖蛋白将减少患病者的氧化应激 心该项目旨在操纵奥赖通道，以减少和逆转心脏功能恶化 单位：瑞士法郎。我们计划通过追求以下具体目标来测试我们的中心假设：目标1：测试假设 Orai 1-和Orai 3-构型具有不同的空间定位、激活机制和下游 基因程序目的2：检验Orai 1或Orai 3的选择性基因消融减弱心脏 肥大并延迟向CHF的转变。目的3：检验肥大细胞的失活 在已建立的心脏肥大期间，通过奥赖基因消融的信号级联可防止向CHF的转变 并改善氧化应激。这项工作将导致阐明的分子机制，奥赖（s） 调节心脏功能;将奥赖鉴定为CHF的新介质;可能确定新的策略 旨在逆转或延迟CHF中出现的氧化应激和功能紊乱。

Abstract Congestive heart failure (CHF) is a major health problem in the USA that affects about 5.7 million Americans. The incidence of CHF is steadily increasing as the general population ages. The national cost of CHF is estimated around $30.7 billion each year. Although the mortality rate and the economic impact of CHF are high, the detailed molecular mechanisms underlying its progression remain unresolved. Understanding the fundamental processes that drive cardiac functional and structural deterioration is essential for developing novel therapies to more fundamentally affect disease progression. The stress-induced cardiac hypertrophy is an essential step in the pathogenesis of many forms of CHF, and its suppression is a viable target for therapeutic intervention. Stromal interaction molecule1 and 2 (STIM1, STIM2) and its molecular partners Orai proteins (Orai1, Orai2, and Orai3) constitute the store-operated Ca2+ channel (SOCC) and are surfacing as new potential therapeutic targets against pathological heart hypertrophy. Results from our published work provide strong evidence, that STIM1 forms Ca2+ microdomains that control cardiac growth via signaling that alters the cytoskeleton and pro-hypertrophic gene program. However, Orai(s) contribution to the progression of the failing heart is unknown. We have generated cardiac-specific Orai1 and Orai3 knockout mice and find that Orai1 associated with Ca2+\calmodulin pathway, while Orai3 is associated prevalently with the PI3K/AKT pathway. We hypothesize that Orai1- and Orai3-dependent Ca2+ signaling are distinct but together orchestrate the cardiac hypertrophic response. Dysregulation of cardiac Ca2+ and oxidative stress appear to be symbiotic in CHF, a corollary to this hypothesis is that selective inhibition of Orai proteins will reduce oxidative stress of the diseased heart. This project seeks to manipulate Orai channels to decrease and reverse cardiac functional deterioration in CHF. We plan to test our central hypothesis by pursuing the following specific aims: Aim 1: Test the hypothesis that Orai1- and Orai3-configurations have different spatial localizations, activation mechanisms, and downstream gene programs. Aim 2: Test the hypothesis that selective genetic ablation of Orai1 or Orai3 attenuates cardiac hypertrophy and delays the transition to CHF. Aim 3: Test the hypothesis that inactivation of hypertrophic signaling cascades by Orai gene ablation during established cardiac hypertrophy prevents the transition to CHF and improves oxidative stress. This work will lead to elucidation of the molecular mechanism by which Orai(s) regulates heart function; the identification of Orai as a novel mediator of CHF; potentially identify new strategies aimed at reversing or delay the oxidative stress and functional derangements seen in CHF.