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

• 批准号: 8801613
• 负责人: Babak Razani
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/8801613
• 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; Foam Cells; Functional disorder; Future; Genes; Goals; 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; human FRAP1 protein; in vivo; insight; interest; lipid metabolism; mTOR Inhibitor; macrophage; member; mortality; mouse model; novel; overexpression; oxidized low density lipoprotein; programs; public health relevance; receptor mediated endocytosis; response; tool; transcription factor; treatment strategy; uptake

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(申请人提供)：动脉粥样硬化性血管疾病仍然是美国的主要死亡原因，大多数死亡原因是冠状动脉疾病和心肌梗死。改变危险因素，如降低高脂血症，构成了这种令人烦恼的疾病可用的唯一治疗策略。因此，有一个活跃的 努力识别提供机械洞察力的罪魁祸首细胞过程。最近关于巨噬细胞特异性自噬缺陷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。溶酶体具有处理外源性物质(如过量的致动脉粥样硬化脂类)和内源性货物(包括功能失调的蛋白质和细胞器)的独特作用。由于动脉粥样硬化环境对巨噬细胞溶酶体的影响知之甚少，我们的目的是测试溶酶体功能障碍是脂代谢的产物这一概念，并评估改善这一影响的新方法。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类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，TFEB是唯一已知的能够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信号密切相关，经典的mTOR抑制剂雷帕霉素可以诱导溶酶体的生物生成，同时减少巨噬细胞功能障碍和动脉粥样硬化。了解脂代谢和溶酶体生物发生之间的联系对于了解斑块的进展具有重要意义。我们建议验证一种假设，即由转录因子TFEB介导的巨噬细胞溶酶体生物发生是动脉粥样硬化过程中的一种重要的代偿反应，并具有动脉粥样硬化保护作用。各种能够解剖TFEB在巨噬细胞中作用的小鼠模型将作为体外和体内解决这一假说的研究工具。