ARC REGULATES MITOCHONDRIAL DEATH SIGNALING IN HEART

ARC 调节心脏线粒体死亡信号

• 批准号: 6821677
• 负责人: MICHAEL T CROW
• 金额: $ 38.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6821677
• 关键词: Bax gene /protein; Golgi apparatus; apoptosis; biological signal transduction; calcium flux; cardiac myocytes; cysteine endopeptidases; enzyme activity; fluorescence microscopy; gene expression; heart cell; laboratory rat; mitochondria; sarcoplasmic reticulum

DESCRIPTION (provided by applicant): Cardiac cell loss is a prominent pathological feature associated with a number of cardiovascular disorders, including myocardial infarction, ischemia/reperfusion, chronic ischemia, and heart failure. ARC (Apoptosis Repressor with CARD/Caspase Recruitment Domain) is a recently identified muscle-specific repressor of cell death. It was originally identified as a protein that interacts with and regulates the activity of initiator caspase 8 which is associated with death receptor (TNFa, Fas) signaling. Our published and preliminary data indicate that there are additional targets for cardioprotection by ARC involving both caspase-dependent and -independent pathways. These targets are the intrinsic death signaling pathways of two major intracellular organelles, the mitochondria and the endoplasmic reticulum/Golgi complex. ARC is present in both subcellular fractions containing these organelles and staining reveals an association of ARC with the ER/developing sarcoplasmic reticulum (SR) of neonatal cardiomyocytes and a striated transverse distribution in adult cardiac muscle fibers that overlaps extensively with the SR. We hypothesize that ARCs structural association with the ER/SR and its close functional association with mitochondria are what is responsible for its ability to suppress a variety of intrinsic death stimuli, often intervening at the earliest stages in death signaling. In the mitochondria, we hypothesize that ARC interferes with BAX translocation/activation, while in the ER/SR it acts as an integral component of the protective arm of the endogenous ER stress response program. To test these hypotheses, we propose the following specific aims: Specific Aim #1 will define the molecular mechanism by which ARC inhibits BAX-induced and BAX associatedcell death as well as the functional significance of its association with a critical regulator of the mitochondrial fusion/fission apparatus. Specific Aim #2 will establish whether ARC is part of the ER stress response known as the unfolded protein response (UPR), what role it plays in ER preconditioning, and whether it suppresses the ER-specific initiator caspase 12. Specific Aim #3 will define ARC's role in regulating the apoptotic crosstalk between the ER/SR and mitochondrial death pathways through its effects on calcium dynamics and initiator caspase activation in response to hypoxia. The studies proposed will define the critical role of ARC in the management of the mitochondrial and ER/Golgi stress responses to cellular injury in the heart.

描述（由申请人提供）：心脏细胞损失是与许多心血管疾病有关的重要病理特征，包括心肌梗塞，缺血/再灌注，慢性缺血和心力衰竭。 ARC（带卡/caspase募集域的凋亡阻遏物）是最近确定的细胞死亡的肌肉特异性阻遏物。它最初被鉴定为与与死亡受体（TNFA，FAS）信号相关的引发剂caspase 8相互作用并调节活性的蛋白质。我们发表的和初步的数据表明，通过涉及caspase依赖性和非依赖性途径的ARC有其他靶标的其他目标。这些靶标是两个主要细胞内细胞器的内在死亡信号通路，即线粒体和内质网/高尔基体复合物。在包含这些细胞器的两个亚细胞级分中存在ARC，并揭示了新生儿心肌细胞的ER/发育中的肌浆网（SR）的缔合，成人心肌纤维中的横向横向分布与SR广泛重叠。我们假设ARCS与ER/SR的结构关联及其与线粒体的紧密功能关联是其抑制各种内在死亡刺激的能力的原因，通常是在死亡信号传导中最早介入的。在线粒体中，我们假设ARC会干扰Bax易位/激活，而在ER/SR中，它充当了内源性ER应力响应程序的保护臂的组成部分。为了检验这些假设，我们提出了以下特定目的：特定目的＃1将定义分子机制，通过该机制，ARC抑制Bax诱导的和Bax相关的病情死亡以及其与线粒体融合/裂变仪的关键调节剂相关性的功能意义。具体目标＃2将确定ARC是否是ER应力反应的一部分，称为展开的蛋白质响应（UPR），它在ER预处理中的作用以及它是否抑制了ER特异性的启动器caspase 12。具体目标＃3将定义ARC在ER/SR和Mitochrial Dregtial Dregtial casp之间的响应中的作用，从而定义了ARC在casp case的响应中的作用。缺氧。提出的研究将定义ARC在心脏中细胞损伤的线粒体和ER/GOLGI应激反应的管理中的关键作用。