Dissecting the Impact of Dietary Protein on Macrophage mTOR Signaling and Atherosclerosis

剖析膳食蛋白质对巨噬细胞 mTOR 信号传导和动脉粥样硬化的影响

• 批准号: 10446622
• 负责人: Bettina Mittendorfer
• 金额: $ 78.44万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10446622
• 关键词: Address; Adult; Adverse effects; Affect; Amino Acids; Animal Model; Animal Sources; Animals; Arterial Fatty Streak; Atherosclerosis; Biological Assay; Blood Vessels; Blood specimen; Carbohydrates; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Culture System; Cells; Characteristics; Cholesterol; Clinical; Consumption; Data; Diet; Dietary Proteins; Dose; Dyslipidemias; Evaluation; FRAP1 gene; Genetically Engineered Mouse; Goals; Health; Human; Immune; Impairment; In Vitro; Ingestion; Intake; Knockout Mice; Lead; Lesion by Morphology; Leucine; Liquid substance; Mediating; Mitochondria; Morbidity - disease rate; Mus; Myocardial Infarction; Necrosis; Obesity; Pathogenesis; Pathway interactions; Persons; Pharmacology; Plant Proteins; Plant Sources; Plasma; Population; Proteins; Public Health; Risk; Risk Factors; Rupture; Signal Transduction; Societies; Stroke; Testing; Therapeutic; Therapeutic Intervention; Thinness; Translating; United States; Vascular Plant; Woman; Work; atherogenesis; burden of illness; cancer clinical trial; cancer therapy; cardiovascular disorder risk; cytotoxic; dietary; dietary guidelines; in vivo; inhibitor; insight; macrophage; men; monocyte; mortality; mouse model; novel; prevent; protein aggregation; protein intake; response; saturated fat; uptake; western diet

Project Summary / Abstract Atherosclerosis is the underlying cause of the majority of cardiovascular diseases, including myocardial infarction and strokes, and results in tremendous morbidity and mortality. A Western-type diet is a major risk factor for atherosclerosis because of the high saturated fat, cholesterol, and refined carbohydrate contents. Dietary strategies to reduce cardiovascular disease burden therefore focus on restriction of saturated fat, cholesterol, and refined carbohydrates whereas “lean” protein intake is recommended and has become popular. However, results from studies conducted in animal models suggest high dietary protein intake is also atherogenic. Our extensive preliminary data in animal models show that dietary protein increases atherosclerotic plaque formation and size and promotes necrotic core formation, a characteristic of rupture-prone plaques. The goal of the current proposal is to provide deeper insights into the relationship between protein intake and the pathogenesis of atherosclerosis by studying the mechanisms involved in protein-mediated atherogenesis and formation of necrotic plaques. Our overarching hypothesis is that high protein intake drives atherosclerosis via leucine-mediated mTORC1 signaling in macrophages, which inhibits macrophage mitophagy and aggrephagy and stimulates macrophage proliferation. Furthermore, we hypothesize that proteins from animal sources are more atherogenic than proteins from plant sources, because animal proteins contain more leucine than plant proteins. We will test these hypotheses by using a sophisticated array of experimental strategies, including assays in primary macrophages and human monocyte-derived macrophages and genetically engineered mouse models. In addition, we will begin to translate the results obtained in vitro and in animals to people, and explore approaches to pharmacologically target the pro-atherogenic pathways as novel cardiovascular therapeutics. Our proposal represents a paradigm shift in how a Western-type diet affects vascular health which has important implications since many adults in Western societies consume excess protein and dietary protein is heavily marketed for its presumed beneficial health effects.

项目概要/摘要 动脉粥样硬化是大多数心血管疾病的根本原因，包括心肌病 梗塞和中风，并导致巨大的发病率和死亡率。西式饮食是主要风险 由于饱和脂肪、胆固醇和精制碳水化合物含量高，因此成为动脉粥样硬化的因素。 因此，减少心血管疾病负担的饮食策略侧重于限制饱和脂肪， 胆固醇和精制碳水化合物，而建议摄入“瘦”蛋白质，并且已经变得流行。 然而，在动物模型中进行的研究结果表明，高膳食蛋白质摄入量也对 致动脉粥样硬化。我们在动物模型中的大量初步数据表明，膳食蛋白质会增加动脉粥样硬化 斑块的形成和大小，并促进坏死核心形成，这是易破裂斑块的一个特征。这 当前提案的目标是更深入地了解蛋白质摄入量与 通过研究蛋白质介导的动脉粥样硬化形成机制和 坏死斑块的形成。我们的首要假设是，高蛋白质摄入通过以下途径导致动脉粥样硬化： 巨噬细胞中亮氨酸介导的 mTORC1 信号传导，抑制巨噬细胞线粒体自噬和聚集吞噬 并刺激巨噬细胞增殖。此外，我们假设来自动物的蛋白质是 比植物来源的蛋白质更容易导致动脉粥样硬化，因为动物蛋白比植物蛋白含有更多的亮氨酸 蛋白质。我们将通过使用一系列复杂的实验策略来测试这些假设，包括 原代巨噬细胞和人单核细胞衍生的巨噬细胞以及基因工程小鼠的测定 模型。此外，我们将开始将体外和动物身上获得的结果转化为人类，并探索 药理学上针对促动脉粥样硬化途径作为新型心血管治疗方法的方法。我们的 该提案代表了西式饮食如何影响血管健康的范式转变，这具有重要意义 影响，因为西方社会的许多成年人消耗了过量的蛋白质，而饮食中的蛋白质含量很高 以其假定的有益健康作用而销售。