Endothelial Cell Respiration in Atherosclerotic Plaque Erosion

动脉粥样硬化斑块糜烂中的内皮细胞呼吸

基本信息

批准号：
10586227
负责人：
Dario Fernando Riascos Bernal
金额：
$ 44.24万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586227
关键词：
3-Dimensional Acceleration Acute Address Affect Anti-Inflammatory Agents Antioxidants Area Arterial Fatty Streak Arteries Atherosclerosis Blood Vessels Blood coagulation Carotid Arteries Cause of Death Cell Death Cell Line Cell Proliferation Cell Respiration Cell Survival Cell physiology Cellular Metabolic Process Cessation of life Clinical Clinical Trials Closure by clamp Coagulation Process Complex Coronary Coronary Arteriosclerosis Coronary heart disease Data Development Endothelial Cells Endothelium Equilibrium Evaluation Event Functional disorder Genetic Heart Heart Diseases Homeostasis Human Hyaluronan Hyperglycemia Hyperlipidemia Impairment In Vitro Incidence Inflammatory Infiltrate Injury Intrinsic factor Knowledge Metabolism Methods Mitochondria Modeling Molecular Molecular and Cellular Biology Mus Myocardial Infarction NADH NADH dehydrogenase (ubiquinone)Natural regeneration Outcome Oxygen Consumption Predisposition Process Production Proliferating Recovery Research Project Grants Research Proposals Respiration Rupture Site Surface Testing Thrombosis Toll-like receptors United States acute coronary syndrome angiogenesis atherosclerotic plaque rupture cell growth cell motility comparative design endothelial repair extracellular healing human migration improved injury and repair innovation mature animal metabolomics migration mitochondrial dysfunction mitochondrial metabolism molecular phenotype monolayer mouse genetics neutrophil pharmacologic prevent repaired stem three-dimensional visualization thrombotic tool

项目摘要

Endothelial Cell Respiration in Atherosclerotic Plaque Erosion Heart disease is the number one cause of death in the United States and worldwide. Coronary artery disease, the most common type of heart disease, is the root cause of acute coronary syndromes, and accounts for 7.4 million deaths per year globally. Nearly all these events stem from atherosclerotic plaque rupture or erosion. While knowledge of plaque rupture has improved in recent decades, comparatively little is known about plaque erosion and its underlying molecular mechanisms – despite recent recognition that it may cause from 25 to 60% of acute coronary syndromes and is increasing in incidence. Plaque erosion is defined by loss of endothelial cells (ECs) leading to thrombosis in the absence of plaque rupture. The pathophysiology of erosion is largely unexplored; the few studies on this topic focus on extrinsic factors that induce EC loss. However, most erosions are clinically silent, which suggests that eroded regions usually heal well enough to prevent an acute coronary syndrome. Notably, the molecular mechanisms underlying repair in plaque erosion are unknown. Our research proposal will study EC intrinsic factors that may change the likelihood that ECs will be lost to death or desquamation, or will contribute to repair, in particular, looking at mitochondrial mechanisms that are unexplored in this setting. During angiogenesis, mitochondrial respiration and metabolism support EC proliferation and migration by mechanisms other than ATP production. We hypothesize that EC respiration is required to support endothelial homeostasis and promote repair during re-endothelialization and plaque erosion. Using tools of molecular and cellular biology and mouse genetics, we will evaluate: a) whether EC respiration promotes cellular activities relevant for endothelial repair of eroded plaques, and unveil underlying molecular mechanisms, b) whether EC respiration supports arterial homeostasis or promotes re- endothelialization after arterial denudation, and c) whether EC respiration oposses plaque erosion or supports re-endothelialization of eroded plaques. Our studies will also incorporate an innovative method to study the endothelium in three-dimensions, and include the evaluation of human atherosclerotic plaques. This research project will bring a new perspective to the nascent field of plaque erosion pathophysiology, focused on mitochondria and cell metabolism, which may open new avenues to prevent or treat acute coronary syndrome.

动脉粥样硬化斑块中的内皮细胞呼吸心脏病是美国和全球死亡的第一大原因。冠状动脉动脉疾病是心脏病的最常见类型，是急性冠状动脉的根本原因综合征，全球每年占740万人死亡。几乎所有这些事件来自动脉粥样硬化斑块破裂或侵蚀。同时知道斑块破裂有所改善近几十年来，关于斑块侵蚀及其基础知之甚少分子机制 - 最近认识到它可能导致25％至60％的急性冠状动脉综合征，发病率正在增加。斑块侵蚀是通过丢失来定义的在没有斑块破裂的情况下，内皮细胞（EC）导致血栓形成。这侵蚀的病理生理基本上是意外的。关于此主题的少数研究集中于外部影响EC损失的因素。但是，大多数侵蚀在临床上是沉默的，这表明 eoded区域通常足够良好，以防止急性冠状动脉综合征。值得注意的是斑块侵蚀中修复的分子机制尚不清楚。我们的研究建议将研究EC的内在因素，这些因素可能会改变EC将失去死亡或脱离或将有助于维修，特别是查看线粒体机制在这种情况下这是出乎意料的。在血管生成期间，线粒体呼吸和代谢支持EC的增殖和通过ATP生产以外的机制迁移。我们假设需要EC呼吸以支持内皮稳态并促进在重新皮层化和牙菌斑侵蚀期间进行修复。使用分子和细胞的工具生物学和小鼠遗传学，我们将评估：a）EC呼吸是否促进细胞与侵蚀斑块的内皮修复相关的活动，并揭示了分子的基础机制，b）EC呼吸是支持动脉稳态还是促进重新动脉剥落后的内皮化，c）EC呼吸是否渗透斑块侵蚀或支持侵蚀斑块的重新皮层化。我们的研究还将结合在三维中研究内皮的创新方法，包括评估人动脉粥样硬化斑块。该研究项目将为斑块侵蚀病理生理学的新生场，重点是线粒体和细胞代谢，这可能会开放新的途径，以预防或治疗急性冠状动脉综合征。