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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.

动脉粥样硬化斑块侵蚀中的内皮细胞呼吸作用