Defining the roles of Orai3 channel in cardiomyocytes and cardiomyopathy.

定义 Orai3 通道在心肌细胞和心肌病中的作用。

基本信息

项目摘要

Abstract Dilated cardiomyopathy (DCM) is a severe condition, often idiopathic, that results in ventricular enlargement and progressive systolic dysfunction. While usually treated with a combination of medications or using implantable devices, cardiac transplantation is typically the ultimate treatment for DCM. The precise mechanisms leading to ventricular dilatation and dysfunction are not well understood. However, during the last few years, attention has focused on abnormalities of contractile and structural myocardial proteins and disorders of cardiac energy metabolism. We identified Orai3, a Ca2+-selective ion channel and a member of the store-operated Ca2+ channels (SOCC), as a critical proactive factor required for maintenance of postnatal cardiac function. The goal of this proposal is to investigate the roles of Orai3-mediated Ca2+ entry and associated molecular mechanisms in cardiomyocytes. To pursue our goal, we have generated several lines of cardiomyocyte-specific Orai3 knockout (Orai3cKO) mice. While constitutive Orai3cKO mice are fertile and viable, they nevertheless develop DCM that closely resembles many of the anatomical, pathophysiological, and clinical features of human DCM culminating in heart failure (HF) and premature death. We discovered through our preliminary research that Orai3-deficient cardiomyocytes exhibited loss of myofiber integrity and ultrastructural abnormalities associated with severe dysregulation of mitochondrial proteins involved in oxidative metabolism and autophagy. Our preliminary data strongly indicate that the Orai3 channel is an essential regulator of cardiac muscle function, and the data provide evidence linking Orai3-mediated Ca2+ signaling to sarcomere cell integrity and bioenergetics balance. We hypothesize that Orai3-mediated Ca2+ entry activates genetic programs through Ca2+ sensitive pathways that promote survival of post-natal cardiomyocytes. We plan to test our hypothesis by pursuing the following Specific Aims: Aim 1: To characterize the DCM phenotype following loss of Orai3 expression in the adult myocardium; Aim 2: To elucidate mechanisms by which Orai3 loss leads to cardiac function deterioration and DCM by analyzing inducible Orai3cKO mice; and Aim 3: To test the hypothesis that Orai3-mediated Ca2+ entry regulates mitochondrial metabolism. This work will lead to discovery of the molecular mechanisms by which Orai3 regulates heart function; identification of Orai as a novel mediator of DCM; and potential identification of new strategies aimed at reversing or delaying the metabolic and functional derangements seen in HF.
摘要 扩张型心肌病(DCM)是一种严重的疾病,通常是特发性的,会导致脑室扩大。 和进行性收缩功能障碍。虽然通常使用药物的组合治疗或使用 心脏移植通常是扩张型心肌病的终极治疗方法。精确的机械装置 导致脑室扩张和功能障碍的原因还不是很清楚。然而,在过去的几年里, 人们关注的焦点是心肌收缩和结构蛋白的异常以及心脏疾病。 能量代谢。我们鉴定了Orai3,一种钙离子选择性离子通道,也是商店操作的钙离子通道的一员 通道(SOCC),作为维持出生后心脏功能所需的关键的主动因素。目标是 研究Orai3介导的钙离子内流的作用及其相关的分子机制 在心肌细胞中。为了实现我们的目标,我们已经产生了几个心肌细胞特异的Orai3系 基因敲除(Orai3cKO)小鼠。虽然构成Orai3cKO的小鼠可以生育和存活,但它们仍会发展为DCM 这与人类扩张性心肌病的许多解剖、病理生理学和临床特征非常相似。 最终导致心力衰竭(HF)和过早死亡。我们通过前期调研发现, Orai3基因缺陷的心肌细胞表现为肌纤维完整性丧失和相关的超微结构异常 参与氧化代谢和自噬的线粒体蛋白严重失调。我们的 初步数据有力地表明,Orai3通道是心肌功能的重要调节因子,并且 这些数据提供了将Orai3介导的钙信号与肌节细胞完整性和生物能量学联系起来的证据 平衡。我们假设Orai3介导的钙离子进入通过钙离子激活遗传程序 促进出生后心肌细胞存活的敏感途径。我们计划通过以下方式来检验我们的假设 追求以下具体目标:目标1:确定Orai3缺失后DCM的表型特征 目的2:阐明Orai3缺失导致心脏病变的机制 通过分析可诱导的Orai3cKO小鼠的功能恶化和DCM;以及目标3:检验假设 Orai3介导的钙离子内流调节线粒体代谢。这项工作将导致分子的发现 Orai3调节心脏功能的机制;确认Orai是扩张型心肌病的新介体;以及 可能确定旨在逆转或延缓代谢和功能的新策略 在HF中看到的精神错乱。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mapping the Proximity Interaction Network of STIM1 Reveals New Mechanisms of Cytoskeletal Regulation.
  • DOI:
    10.3390/cells10102701
  • 发表时间:
    2021-10-09
  • 期刊:
  • 影响因子:
    6
  • 作者:
    Gammons J;Halpage J;Mancarella S
  • 通讯作者:
    Mancarella S
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Salvatore Mancarella其他文献

Salvatore Mancarella的其他文献

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{{ truncateString('Salvatore Mancarella', 18)}}的其他基金

Defining the roles of Orai3 channel in cardiomyocytes and cardiomyopathy.
定义 Orai3 通道在心肌细胞和心肌病中的作用。
  • 批准号:
    10031843
  • 财政年份:
    2020
  • 资助金额:
    $ 38万
  • 项目类别:
Defining the roles of Orai3 channel in cardiomyocytes and cardiomyopathy.
定义 Orai3 通道在心肌细胞和心肌病中的作用。
  • 批准号:
    10238106
  • 财政年份:
    2020
  • 资助金额:
    $ 38万
  • 项目类别:
Role of Orai in pathological cardiac remodeling
Orai 在病理性心脏重塑中的作用
  • 批准号:
    10002616
  • 财政年份:
    2019
  • 资助金额:
    $ 38万
  • 项目类别:
STIM-Dependent Signaling in Cardiac Pathophysiology
心脏病理生理学中的 STIM 依赖性信号传导
  • 批准号:
    8509258
  • 财政年份:
    2013
  • 资助金额:
    $ 38万
  • 项目类别:
STIM-Dependent Signaling in Cardiac Pathophysiology
心脏病理生理学中的 STIM 依赖性信号传导
  • 批准号:
    8712547
  • 财政年份:
    2013
  • 资助金额:
    $ 38万
  • 项目类别:
Store Operated Calcium Channels Function in Vascular Smooth Muscle
血管平滑肌中存储操纵的钙通道功能
  • 批准号:
    8142100
  • 财政年份:
    2010
  • 资助金额:
    $ 38万
  • 项目类别:
Store Operated Calcium Channels Function in Vascular Smooth Muscle
血管平滑肌中存储操纵的钙通道功能
  • 批准号:
    8320293
  • 财政年份:
    2010
  • 资助金额:
    $ 38万
  • 项目类别:
Store Operated Calcium Channels Function in Vascular Smooth Muscle
血管平滑肌中存储操纵的钙通道功能
  • 批准号:
    8005340
  • 财政年份:
    2010
  • 资助金额:
    $ 38万
  • 项目类别:

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