Role of Orai in pathological cardiac remodeling

摘要 充血性心力衰竭(CHF)是美国一个主要的健康问题，影响着大约570万美国人。 随着普通人群的老龄化，心力衰竭的发病率正在稳步上升。瑞士法郎的国家成本是 据估计，每年约为307亿美元。尽管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是开发新的 治疗更能从根本上影响疾病的进展。应激诱导的心肌肥厚是一种 在多种形式的充血性心力衰竭发病机制中的重要步骤，其抑制是一个可行的治疗靶点 干预。基质相互作用分子1和2(STIM1、STIM2)及其分子伴侣Orai蛋白 (ORAI1、ORAI2和ORAI3)构成了存储操作的钙通道(SOCC)，并作为新的潜力浮出水面 针对病理性心脏肥厚的治疗靶点。我们发表的工作成果提供了强有力的 有证据表明，STIM1形成了钙微域，通过改变信号来控制心脏生长。 细胞骨架和促肥大基因计划。然而，大井(S)的失败为进步做出了贡献 心是未知的。我们已经培育出心脏特异的Orai1和Orai3基因敲除小鼠，并发现Orai1 Orai3与PI3K/AKT通路有关。我们 假设Orai1和Orai3依赖的钙信号是不同的，但共同协调心脏 肥大反应。慢性心力衰竭时，心肌钙调节失调和氧化应激似乎是共生的。 这一假设的推论是，选择性抑制Orai蛋白将减少患者的氧化应激 心。该项目试图通过操纵Orai通道来减少和逆转心脏功能恶化 以瑞士法郎计算。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 Orai1和Orai3构型具有不同的空间局部化、激活机制和下游 基因程序。目的2：验证选择性基因消融Orai1或Orai3可减弱心脏功能的假设 肥大并延迟向充血性心力衰竭的转变。目的3：检验肥厚失活的假说 在已建立的心肌肥厚期间，Orai基因消融导致的信号级联可阻止向CHF的转变 并改善氧化应激。这项工作将有助于阐明Orai(S) 调节心脏功能；确认Orai是CHF的新介质；潜在地确定新的策略 旨在逆转或延缓CHF中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.