Mechanisms and Consequences of Stress-Induced Macrophage Death in Atherosclerosis

动脉粥样硬化中应激引起的巨噬细胞死亡的机制和后果

• 批准号: 8800564
• 负责人: Ira A Tabas
• 金额: $ 39.4万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800564
• 关键词: Acute; Address; Affect; Animal Model; Animals; Apoptosis; Apoptotic; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Platelets; Calcium; Cause of Death; Cell Death; Cellular biology; Cessation of life; Clinical; Coronary; Coronary Arteriosclerosis; Data; Disease; Down-Regulation; Drug Targeting; Employee Strikes; Endoplasmic Reticulum; Etiology; Event; Exposure to; Fatty acid glycerol esters; Feeds; Foundations; Future; Generations; Goals; Health; Heart Diseases; Human; Individual; Induction of Apoptosis; Inflammation; Knowledge; Lead; Lesion; Leukocytes; Link; Measures; Mediating; Minority; Mitochondria; Molecular; Mus; Myocardial Infarction; Necrosis; Nitrogen; Organ; Oxidative Stress; Oxygen; Pathway interactions; Play; Population; Process; Proteins; Risk Factors; Role; Signal Pathway; Societies; Stress; Stroke; Sudden Death; Testing; Therapeutic; Thrombosis; Vascular blood supply; Work; arm; base; caspase-8; catalase; cell type; endoplasmic reticulum stress; fascinate; feeding; high risk; in vivo; insight; macrophage; mouse model; novel; novel therapeutics; prevent; stressor; therapeutic target; translational study; uptake; western diet

DESCRIPTION (provided by applicant): Atherosclerotic vascular disease is the leading cause of death in most populations. Only a minority of atherosclerotic lesions actually cause clinical disease, and a key, distinguishing feature of those that do is plaque necrosis. The overall objective of this proposal is to gain in-depth understanding of the signaling pathways involved in plaque necrosis, with the ultimate goal of developing novel therapeutic measures for high-risk individuals. Our and others' previous work has provided evidence that plaque necrosis and inflammation are promoted by leukocyte/macrophage (Mf) apoptosis in advanced lesions, a major cause of which is exposure to endoplasmic reticulum (ER) stress and reactive oxygen/nitrogen species. However, there are critical gaps in our understanding of the mechanisms that trigger these stress pathways and how they lead to apoptosis. Based on new data in the PI's lab, the proposal will address these gaps by focusing on new upstream and downstream signaling pathways involved in Mf apoptosis. We hypothesize that oxidative stress originating from the mitochondria, referred to as "mitoOS," plays a key upstream role and that a novel Bax/Bak-caspase 8 (casp8) pathway plays a major downstream role in advanced lesional Mf apoptosis and plaque necrosis. In Aim 1, we will elucidate how mitoOS induces the ER- stress apoptosis effector CHOP; evaluate whether mitoOS pathways in addition to CHOP promote Mf apoptosis; and explore the role of 2 inducers of mitoOS, Drp1 and mitochondrial Ca2+ uptake. Most importantly, we will study fat-fed Ldlr-/- mice in which (a) Mfs express mitochondria-targeted catalase, which suppresses mitoOS and apoptosis; and (b) Drp1 is absent in Mfs, which blocks mitochondrial fission, mitoOS, and apoptosis. In Aim 2, we will explore the mechanism of the new Bax/Bak-casp8 apoptosis pathway and investigate links to the mitoOS-CHOP pathway in Aim 1. We will then test causation in advanced atherosclerosis, following the same overall strategy as in Aim 1, using two unique models: mice whose Mfs lack Bax/Bak and mice expressing a form of casp8 that specifically blocks its role in apoptosis. We will also explore the presence of act-casp8 in advanced human atheromata. These combined studies will add significantly to our knowledge of how clinically dangerous atherosclerotic plaques form and how the process may be therapeutically suppressed. Summary of Relevance: Coronary artery disease is the leading killer in most populations. Current therapies are focused on risk factor reduction. A complementary approach directly targeting lesion progression could be extremely valuable in decreasing heart disease. This proposal is focused on specific processes that are known to promote atherosclerosis progression and which, with knowledge gained herein, could be excellent drug targets.

描述（由申请人提供）：动脉粥样硬化血管疾病是大多数人群的主要死亡原因。只有少数动脉粥样硬化病变实际上会引起临床疾病，而那些做的关键特征是斑块坏死。该提案的总体目的是深入了解与斑块坏死有关的信号传导途径，其最终目标是为高危个体开发新的治疗措施。我们和其他人以前的工作提供了证据表明，牙菌性坏死和炎症是通过白细胞/巨噬细胞（MF）凋亡在晚期病变中促进的，这是暴露于内质网胁迫（ER）应激（ER）胁迫和活性氧/氮素物种的主要原因。但是，我们对触发这些压力途径及其如何导致凋亡的机制的理解存在关键差距。根据PI实验室中的新数据，该提案将通过关注MF凋亡涉及的新上游和下游信号通路来解决这些差距。我们假设源自线粒体的氧化应激，称为“线粒体”，扮演着重要的上游角色，而新颖的Bax/Bak-caspase 8（casp8）途径在晚期的MF proptosis和Plaque necrosis中起着主要的下游作用。在AIM 1中，我们将阐明Mitoos如何诱导ER应激凋亡效应子章。评估除CHOP之外的Mitoos途径是否促进了MF凋亡；并探索2个诱导剂，DRP1和线粒体Ca2+摄取的作用。最重要的是，我们将研究脂肪喂养的LDLR - / - 小鼠，其中（a）MFS表达线粒体靶向的过氧化氢酶，从而抑制线粒体和细胞凋亡。 （b）MFS中不存在DRP1，它阻塞了线粒体裂变，线粒体和凋亡。在AIM 2中，我们将探讨新的Bax/Bak-CASP8凋亡途径的机制，并研究AIM 1中与Mitoos-Chop途径的链接。然后，我们将遵循与AIM 1相同的整体策略中的高级动脉粥样硬化策略中的因果关系测试，使用两个独特的模型：MFS缺乏Bax/Bak和Mecot casss casss proms casss promports cassps promspects of cass prompss sects cass seps 1均相同的整体策略。我们还将探索晚期人动脉瘤中ACT-CASP8的存在。这些合并的研究将大大增加我们对临床上危险的动脉粥样硬化斑块的形成以及该过程如何在治疗中抑制的知识。相关性摘要：冠状动脉疾病是大多数人群的主要杀手。当前的疗法集中于降低危险因素。直接靶向病变进展的互补方法对于减少心脏病可能非常有价值。该建议集中于已知促进动脉粥样硬化进展的特定过程，并且在此获得知识可能是极好的药物靶标。