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(申请人提供)：动脉粥样硬化性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真正引起临床疾病，而这些病变的一个关键的、明显的特征是斑块坏死。这项建议的总体目标是深入了解斑块坏死所涉及的信号通路，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，表明晚期病变中的白细胞/巨噬细胞(MF)凋亡促进了斑块坏死和炎症，其主要原因是暴露在内质网(ER)应激和活性氧/氮物种中。然而，在我们对触发这些应激途径的机制以及它们如何导致细胞凋亡的理解上存在着严重的差距。基于PI实验室的新数据，该提案将通过关注涉及MF凋亡的新的上游和下游信号通路来解决这些差距。我们假设起源于线粒体的氧化应激，称为“mitoOS”，在上游发挥关键作用，而一个新的Bax/Bak-caspase 8(Casp8)途径在晚期皮损MF细胞凋亡和斑块坏死中发挥主要下游作用。在目标1中，我们将阐明mitoOS是如何诱导内质网应激凋亡效应因子CHOP的；评估除了CHOP之外的mitoOS通路是否促进了MF的凋亡；并探讨了mitoOS、Drp1和线粒体钙摄取的两种诱导剂的作用。最重要的是，我们将研究脂肪喂养的Ldlr-/-小鼠，在这些小鼠中，(A)MFS表达线粒体靶向过氧化氢酶，它抑制mitoOS和细胞凋亡；(B)MFS中缺少Drp1，它阻止线粒体分裂、mitoOS和细胞凋亡。在目标2中，我们将探索新的Bax/Bak-casp8凋亡途径的机制，并在目标1中调查与mitoOS-CHOP途径的联系。然后，我们将遵循与目标1相同的总体策略，使用两个独特的模型：MFS缺乏Bax/Bak的小鼠和表达某种形式的casp8的小鼠特异性地阻断其在细胞凋亡中的作用，以检验晚期动脉粥样硬化的原因。我们还将探索ACT-casp8在晚期人类动脉粥样瘤中的存在。这些联合研究将大大增加我们对临床上危险的动脉粥样硬化斑块如何形成以及如何从治疗上抑制这一过程的了解。相关性概述：冠状动脉疾病是大多数人的头号杀手。目前的治疗方法主要集中在降低风险因素上。一种直接针对病变进展的补充方法在减少心脏病方面可能非常有价值。这项建议侧重于已知的促进动脉粥样硬化进展的特定过程，根据本文获得的知识，这些过程可能是极好的药物靶点。