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

基本信息

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
项目类别：
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

项目摘要

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，包括心肌梗塞和中风，并导致巨大的发病率和死亡率。西方型饮食是主要风险高饱和脂肪，胆固醇和精制碳水化合物含量，动脉粥样硬化的因素。因此，减少心血管疾病燃烧的饮食策略专注于饱和脂肪的限制，胆固醇和精制的碳水合物，而“瘦”蛋白摄入建议并变得流行。然而，在动物模型中进行的研究的结果表明，饮食中的摄入量也很高动脉粥样硬化。我们在动物模型中广泛的初步数据表明，饮食蛋白会增加动脉粥样硬化牙菌斑的形成和大小并促进坏死核的形成，这是破裂易发的特征。当前建议的目标是对蛋白质摄入与蛋白质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和坏死斑的形成。我们的总体假设是，高蛋白摄入量通过亮氨酸介导的巨噬细胞中的MTORC1信号传导，巨噬细胞抑制了巨噬细胞的线粒体和杂色并刺激巨噬细胞增殖。此外，我们假设动物来源的蛋白质是比植物来源的蛋白质更重要，因为动物蛋白含有比植物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检验这些假设，包括初级巨噬细胞和人类单核细胞衍生的巨噬细胞和基因工程小鼠的测定型号。此外，我们将开始将体外和动物中获得的结果转化为人，并探索作为新颖的心血管疗法，药物的方法以促动脉粥样硬化途径为目标。我们的提案代表西方饮食影响血管健康的范式转变，这具有重要的含义由于西方社会中的许多成年人消耗过量的蛋白质和饮食蛋白质很大因其假定的有益健康影响而销售。