Harnessing the Autophagy-Lysosomal Biogenesis Response in Macrophages to Treat Atherosclerosis

利用巨噬细胞自噬-溶酶体生物发生反应治疗动脉粥样硬化

• 批准号: 10265332
• 负责人: Babak Razani
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265332
• 关键词: Area; Arterial Fatty Streak; Atherosclerosis; Autophagocytosis; Biogenesis; Cardiovascular Diseases; Caring; Cause of Death; Cell Death; Cell physiology; Cells; Cholesterol; Cholesterol Esters; Clinical; Coronary Arteriosclerosis; Crystallization; Data; Deposition; Digestion; Disease; Enzymes; Event; Foam Cells; Functional disorder; Future; Genes; Genetic; Genetic Models; Goals; Heart failure; Hyperlipidemia; Hypertension; In Vitro; Infiltration; Inflammasome; Inflammatory; Investigation; Link; Lipids; Lipoprotein Receptor; Lysosomes; Mammals; Mediating; Medical; Membrane; Mitochondria; Modification; Molecular Chaperones; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Organelles; Organism; Pathogenesis; Pathway interactions; Phagocytosis; Pharmacology; Phenotype; Process; Property; Proteins; Publishing; Reactive Oxygen Species; Reporting; Risk Factors; Role; Signal Transduction; Stroke; System; Techniques; Testing; Therapeutic; Therapeutic Uses; Trehalase; Trehalose; Tropism; United States; Work; atherogenesis; atheroprotective; cytotoxic; in vivo; insight; interest; lipid metabolism; macrophage; military veteran; mortality; novel; novel strategies; overexpression; oxidized low density lipoprotein; protein aggregation; receptor mediated endocytosis; response; sugar; transcription factor; treatment strategy; uptake

Atherosclerosis is the underlying cause of the majority of cardiovascular diseases including myocardial infarction, strokes, and heart failure leading to tremendous morbidity and mortality worldwide. Risk factor modification such as reductions in hyperlipidemia and hypertension constitute 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. Reports of the pro-atherogenic 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. Indeed, this is a primary mechanism by which macrophages can degrade excess lipids and cytotoxic materials present in the atherosclerotic plaque. Various lines of evidence demonstrate a progressive dysfunction in the autophagy-lysosome system of plaque macrophages suggesting that attempts at reprogramming the degradative capacity of macrophages might be a fruitful therapeutic area. Our work with TFEB, the predominant transcription factor regulating autophagy-lysosomal biogenesis, shows that enhancing TFEB function in macrophages leads to reductions in atherosclerosis of mice. In an attempt to harness this pathway therapeutically, we have uncovered a safe and natural sugar called trehalose, able to induce TFEB and autophagy-lysosome biogenesis in macrophages and recapitulate the atheroprotective properties. This raises the prospect of this sugar as a novel and practical therapy. In specific aim 1, we will dissect the mechanisms linking trehalose to macrophage autophagy- lysosomal biogenesis. In specific aim 2, we will determine the predominant autophagic processes in macrophages that underlie trehalose’s ability to reduce atherosclerosis. A major impediment to the therapeutic use of trehalose is degradation by the enzyme trehalase, present in higher organisms including mammals. In specific aim 3, genetic and pharmacological techniques of inhibiting trehalase will be used to determine if trehalose’s effects can be synergized. This proposal will test the hypothesis that trehalose can harness macrophage autophagy-lysosomal biogenesis to treat atherosclerosis.

动脉粥样硬化是大多数心血管疾病的根本原因，包括心肌梗死。 脑梗死、中风和心力衰竭导致世界范围内巨大的发病率和死亡率。危险因素 改变如降低高脂血症和高血压是唯一的治疗策略 可用于治疗这种令人烦恼的疾病。因此，有一个积极的努力，以确定罪魁祸首细胞过程， 提供机械的洞察力。小鼠巨噬细胞特异性血管内皮细胞因子的致动脉粥样硬化表型的报告 自噬缺陷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致动脉粥样硬化脂质和 内源性货物，包括功能失调的蛋白质和细胞器。事实上，这是一个主要的机制， 巨噬细胞可通过该途径降解动脉粥样硬化中存在的过量脂质和细胞毒性物质 斑块各种证据表明，自噬-溶酶体系统的进行性功能障碍， 噬斑巨噬细胞表明，试图重新编程巨噬细胞的降解能力， 可能是一个富有成效的治疗领域。我们的工作与TFEB，主要的转录因子调节 自噬-溶酶体生物发生，表明增强巨噬细胞中的TFEB功能导致自噬-溶酶体生物发生减少。 小鼠的动脉粥样硬化。在试图利用这一途径治疗，我们已经发现了一个安全， 天然糖称为海藻糖，能够在巨噬细胞中诱导TFEB和自噬-溶酶体生物发生， 概括了抗动脉粥样硬化的特性。这提高了这种糖作为一种新颖实用的糖的前景。 疗法在具体目标1中，我们将剖析海藻糖与巨噬细胞自噬的联系机制- 溶酶体生物发生在具体的目标2中，我们将确定主要的自噬过程， 巨噬细胞，海藻糖的减少动脉粥样硬化的能力的基础。治疗的主要障碍 海藻糖的使用是通过存在于包括哺乳动物在内的高等生物中的海藻糖酶降解。在 具体目标3，抑制海藻糖酶的遗传和药理学技术将用于确定是否 海藻糖的作用可以被协同。这一提议将检验海藻糖可以利用 巨噬细胞自噬-溶酶体生物合成治疗动脉粥样硬化。