Cell Death Regulation by Pro-Apoptotic BOK in Cardiomyocytes

心肌细胞中促凋亡 BOK 调节细胞死亡

• 批准号: 9458233
• 负责人: Samuel G Katz
• 金额: $ 43.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9458233
• 关键词: Address; Apoptosis; Apoptotic; Attention; Award; BAX gene; BCL2 gene; Biochemistry; Calcium; Calcium Channel; Calcium Signaling; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cell Death Signaling Process; Cell Survival; Cell physiology; Cells; Cellular Stress; Cessation of life; Development; Dissection; Endoplasmic Reticulum; Equilibrium; Exhibits; Family; Family member; Functional disorder; Genetic; Goals; Heart Diseases; Homeostasis; Homologous Gene; ITPR1 gene; Image; Life; Location; Mediating; Membrane; Methods; Mitochondria; Modeling; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Null Lymphocytes; Organelles; Outer Mitochondrial Membrane; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Stimulus; Stress; Tissues; Work; endoplasmic reticulum stress; heart cell; human disease; inositol 3-phosphate; interdisciplinary approach; mitochondrial membrane; mortality; novel; overexpression; public health relevance; response; subcellular targeting; therapeutic target; uptake

 DESCRIPTION (provided by applicant): Endoplasmic Reticulum (ER) stress-induced cardiomyocyte dysfunction and death are thought to play a central role in the development of numerous cardiovascular diseases. Therefore, understanding the signaling networks that control programmed cell death triggered by ER stress is expected to provide valuable therapeutic targets. The ER stress pathway begins with activation of a tripartite of signal transduction pathways, collectively known as the Unfolded Protein Response (UPR), in an attempt to restore homeostasis. If the damage at the ER is too severe, however, then the UPR triggers apoptosis at the mitochondria through the BCL-2 family of cell death regulators. The signaling network that connects the ER stress to the BCL-2 death machinery has remained largely elusive. Addressing this point, we recently discovered that BOK, unlike its BCL-2 family homologues BAX and BAK, selectively regulates the apoptotic response to ER stress, but not other stimuli. Thus, the overall goal of this proposal is to define the mechanisms by which BOK transmits ER stress to promote apoptosis. Preliminary work supports a non-canonical function for BOK that largely occurs at the ER where it is bound to the inositol-3-phosphate (IP3R) calcium transporter. I propose a multidisciplinary approach that employs genetics, advanced imaging, and biochemistry to focus on the physiologic role of BOK in mediating ER-mitochondrial signaling in cardiomyocytes. In particular, we will examine (1) the finely resolved localization of BOK function, (2) calcium homeostasis and (3) the ER-mitochondria interface under normal and ER stress conditions. The proposed mechanistic dissection of BOK activity will integrate cellular physiology at the ER with the regulation of apoptosis by the BCL-2 family at the mitochondria. Understanding this pathway will likely yield valuable pharmacologic targets to promote cell survival in the face of extreme ER stress and thereby alleviate or eliminate the long term consequences of cell death in cardiovascular diseases.

 描述（由申请人提供）：内质网（ER）应激诱导的心肌细胞功能障碍和死亡被认为在许多心血管疾病的发展中起核心作用。因此，了解控制由ER应激触发的程序性细胞死亡的信号网络有望提供有价值的治疗靶点。内质网应激途径开始于激活三条信号转导途径，统称为未折叠蛋白反应（UPR），试图恢复稳态。然而，如果ER的损伤太严重，那么UPR通过BCL-2家族的细胞死亡调节因子触发线粒体凋亡。连接ER应激与BCL-2死亡机制的信号网络在很大程度上仍然难以捉摸。针对这一点，我们最近发现，BOK，不像它的BCL-2家族同系物BAX和巴克，选择性地调节ER应激的凋亡反应，而不是其他刺激。因此，该建议的总体目标是确定BOK传递ER应激以促进细胞凋亡的机制。初步工作支持BOK的非经典功能，该功能主要发生在ER，在ER中BOK与肌醇-3-磷酸（IP 3R）钙转运蛋白结合。我提出了一个多学科的方法，采用遗传学，先进的成像和生物化学，专注于BOK介导的ER-线粒体信号在心肌细胞中的生理作用。特别是，我们将研究（1）BOK功能的精细定位，（2）钙稳态和（3）正常和ER应激条件下的ER-线粒体界面。所提出的BOK活性的机制解剖将整合ER的细胞生理学与线粒体处BCL-2家族对细胞凋亡的调节。了解这一途径将可能产生有价值的药理学靶点，以促进细胞在极端ER应激下的存活，从而减轻或消除心血管疾病中细胞死亡的长期后果。