THE ROLE OF MACROPHAGE LYSOSOMAL BIOGENESIS IN ATHEROSCLEROSIS

巨噬细胞溶酶体生物发生在动脉粥样硬化中的作用

基本信息

批准号：
8962169
负责人：
Babak Razani
金额：
$ 38.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-04 至 2019-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8962169
关键词：
Address Area Arterial Fatty Streak Atherosclerosis Autophagocytosis Biogenesis Cardiovascular Diseases Cause of Death Cell physiology Cells Cholesterol Complex Coronary Arteriosclerosis Data Deposition Digestion Disease Environment Event Exposure to FRAP1 gene Foam Cells Functional disorder Future Genes Goals Health Hyperlipidemia Impairment In Vitro Infiltration Inflammatory Investigation Learning Link Lipids Lipoprotein Receptor Lysosomes Mediating Mediator of activation protein Modeling Modification Morbidity - disease rate Mus Myocardial Infarction Nuclear Translocation Organelles Pathogenesis Pathway interactions Phagocytosis Phenotype Process Proteins Regulation Reporting Research Risk Factors Role Signal Pathway Signal Transduction Sirolimus Stress Stroke System Testing Therapeutic United States Vascular System atherogenesis atheroprotective base detection of nutrient in vivo insight interest lipid metabolism mTOR Inhibitor macrophage member mortality mouse model novel overexpression oxidized low density lipoprotein programs receptor mediated endocytosis response tool transcription factor treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): Atherosclerotic vascular disease remains the leading cause of death in the United States with the majority of mortality due to coronary artery disease and myocardial infarction. Risk factor modification such as reductions in hyperlipidemia constitutes the only treatment strategy available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes that provide mechanistic insight. Recent reports f the proatherogenic phenotype of mice with a macrophage-specific autophagy deficiency has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique role of processing both exogenous material such as excess atherogenic lipids and endogenous cargo that includes dysfunctional proteins and organelles. Since little is known about the effect of an atherogenic environment on macrophage lysosomes, we aimed to test the notion that lysosomal dysfunction is the product of lipid metabolism and evaluate novel ways to ameliorate this effect. Our preliminary data demonstrate that macrophages develop features of lysosome dysfunction upon exposure to atherogenic lipids. In turn, this lysosomal stress can activate TFEB, the only known transcription factor that can broadly stimulate lysosomal biogenesis and function. The regulation of macrophage TFEB appears to be critically linked to mTOR signaling, buttressed by the observation that the classic mTOR inhibitor Rapamycin can induce lysosomal biogenesis while reducing macrophage dysfunction and atherosclerosis. Understanding the links between lipid metabolism and lysosomal biogenesis has important implications in understanding plaque progression. We propose to test the hypothesis that macrophage lysosomal biogenesis mediated by the transcription factor TFEB is an important compensatory response during atherosclerosis and serves an atheroprotective role. A variety of mouse models capable of dissecting the role of TFEB action in macrophages will serve as the research tools to address this hypothesis both in vitro and in vivo.

描述（由申请人提供）：动脉粥样硬化性血管疾病仍然是美国主要的死亡原因，其中大部分死亡是由于冠状动脉疾病和心肌梗塞造成的。降低高脂血症等危险因素的改变是治疗这种令人烦恼的疾病的唯一治疗策略。因此，有一个活跃的努力识别罪魁祸首的细胞过程，提供机制洞察。最近关于巨噬细胞特异性自噬缺陷的小鼠的致动脉粥样硬化表型的报道重新引起了人们对自噬-溶酶体系统在动脉粥样硬化中的作用的兴趣。溶酶体具有独特的作用，可以处理外源物质（例如过量的致动脉粥样硬化脂质）和内源物质（包括功能失调的蛋白质和细胞器）。由于人们对致动脉粥样硬化环境对巨噬细胞溶酶体的影响知之甚少，因此我们旨在测试溶酶体功能障碍是脂质代谢产物的概念，并评估改善这种影响的新方法。我们的初步数据表明，巨噬细胞在暴露于致动脉粥样硬化脂质时会出现溶酶体功能障碍的特征。反过来，这种溶酶体应激可以激活 TFEB，这是唯一已知的可以广泛刺激溶酶体生物发生和功能的转录因子。巨噬细胞 TFEB 的调节似乎与 mTOR 信号传导密切相关，经典 mTOR 抑制剂雷帕霉素可以诱导溶酶体生物合成，同时减少巨噬细胞功能障碍和动脉粥样硬化的观察结果证实了这一点。了解脂质代谢和溶酶体生物发生之间的联系对于了解斑块进展具有重要意义。我们建议检验以下假设：由转录因子 TFEB 介导的巨噬细胞溶酶体生物合成是动脉粥样硬化期间重要的代偿反应，并发挥动脉粥样硬化保护作用。能够剖析 TFEB 在巨噬细胞中作用的各种小鼠模型将作为研究工具在体外和体内解决这一假设。