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

项目摘要/摘要 动脉粥样硬化是大多数心血管疾病的根本原因，包括心肌梗死 脑梗塞和中风，并导致极大的发病率和死亡率。西式饮食是一大风险 由于高饱和脂肪、胆固醇和精制碳水化合物含量，导致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“瘦肉”蛋白质摄入量被推荐，并已变得流行。 然而，在动物模型中进行的研究结果表明，高饮食蛋白质摄入量也是 会导致动脉粥样硬化。我们在动物模型中的大量初步数据表明，饮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的形成，这是易于破裂的斑块的特征。这个 目前这项提案的目标是对蛋白质摄入量和体重之间的关系提供更深入的见解 通过研究蛋白质介导的动脉粥样硬化发生和发展机制来研究动脉粥样硬化的发病机制 形成坏死斑。我们的主要假设是，高蛋白摄入通过 亮氨酸介导的巨噬细胞mTORC1信号，抑制巨噬细胞的有丝分裂吞噬和聚集吞噬 并刺激巨噬细胞的增殖。此外，我们假设来自动物来源的蛋白质是 比植物来源的蛋白质更容易导致动脉粥样硬化，因为动物蛋白质比植物含有更多的亮氨酸 蛋白质。我们将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、人单核细胞来源的巨噬细胞和基因工程小鼠的检测 模特们。此外，我们将开始将在体外和动物中获得的结果转化为人类，并探索 将促动脉粥样硬化途径作为新的心血管治疗药物的药理靶点。我们的 该提议代表了西式饮食如何影响血管健康的范式转变，这具有重要的意义 暗示因为西方社会的许多成年人摄入过量的蛋白质和大量的饮食蛋白质 以其推定的有益健康效果为卖点。

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.