Noncanonical activities of a tRNA synthetase in metabolism and atherosclerosis-Pr

tRNA 合成酶在代谢和动脉粥样硬化中的非典型活性-Pr

• 批准号: 8792570
• 负责人: PAUL L FOX
• 金额: $ 43.09万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8792570
• 关键词: A Mouse; Adipocytes; Adipose tissue; Adult; Affect; Agonist; Amino Acyl-tRNA Synthetases; Apolipoprotein E; Atherosclerosis; Bacteriophages; Binding; Blood Vessels; Carbohydrates; Cardiovascular Diseases; Cell membrane; Cells; Complex; Coupling; Cyclin-Dependent Kinase 5; Diabetes Mellitus; Diet; Disease; Doctor of Philosophy; Drosophila genus; Economic Burden; Endothelial Cells; Energy Metabolism; Epidemic; Event; Exhibits; Fat Body; Fatty acid glycerol esters; Food; Food Supply; Foxes; Future; Genes; Genetic; Goals; Health; Human; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interferon Type II; Interferons; Investigation; Knock-in Mouse; Knockout Mice; Laboratories; Link; Lipids; Lipoproteins; Mediating; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mus; Obesity; Obesity associated cardiovascular disease; Pathology; Pathway interactions; Phenocopy; Phenotype; Phosphorylation; Phosphotransferases; Process; Proteins; Reducing diet; Regulation; Ribosomal Protein S6 Kinase; Risk Factors; Role; Sclerosis; Signal Pathway; Signal Transduction; Site; System; Tertiary Protein Structure; Testing; Transcript; Translations; Triad Acrylic Resin; United States; Vascular Diseases; Vascular Endothelial Growth Factors; Western World; abstracting; age related; angiogenesis; cell type; dietary restriction; epidoxorubicin glucuronide; fatty acid transport; fatty acid-transport protein; gain of function; genetic selection; glucose metabolism; human FRAP1 protein; in vivo; inhibitor/antagonist; lipid metabolism; long chain fatty acid; loss of function; mTOR protein; macrophage; mimetics; new therapeutic target; novel strategies; paracrine; programs; proline-tRNA; therapeutic target; uncoupling protein 1; upstream kinase; uptake

Project 3 (P3). Noncanonical activities of a tRNA synthetase in metabolism and atherosclerosis Paul L. Fox, Ph.D., Project Leader Project Summary/Abstract The long-term goal of Project 3 is to understand the noncanonical function of an extraordinary tRNA synthetase, the Glu-Pro tRNA synthetase or EPRS, in diet-induced obesity and consequent cardiovascular disease, particularly atherosclerosis. The recent explosive epidemic of obesity, insulin resistance, and cardiovascular disease has begun an unprecedented decline in the health-span of adults in the U.S., and likewise threatens an equally unprecedented economic burden. In 1942, James Neel suggested a possible rationale for the genetic selection of genes causing these pathologies. He posited that metabolic pathways were naturally selected to efficiently store fat and carbohydrate during periods of food scarcity; however, the same genes and pathways are detrimental during periods of plentiful, calorie-rich food supply as in the Western world today. A kinase cascade involving the mammalian target of rapamycin (mTORC1) and ribosomal protein S6 kinase-1 (S6K1) is implicated as a key metabolic pathway regulating food utilization, and is conserved from Drosophila to humans. Despite intense study, the key downstream effector(s) of mTORC1-S6K1, and consequent cell mechanisms that regulate metabolism remains unknown. During the previous Project period, we made fundamental in vitro and in vivo discoveries that revealed phosphorylated EPRS as a key downstream effector of mTORC1-S6K1, regulating post-transcriptional, inflammation-related pathways in macrophages and metabolic pathways in adipocytes. Inflammatory macrophages permeate the more abundant adipocytes in adipose tissue of obese subjects, and EPRS phosphorylation in both cell types by S6K1 might functionally couple these cells, and contribute importantly to obesity-associated cardiovascular disease. To test the role of phospho-EPRS in these processes we have generated genetically-modified EPRS phospho-deficient and phospho-mimetic knock-in mice. Preliminary studies show that phospho-deficient EPRS mice phenocopy S6K1-null mice, e.g., small size and low fat mass, and will permit rigorous investigation of the role of EPRS in mTORC1-S6K1-driven mechanisms in vivo. We propose to test the following hypothesis: Phospho-EPRS is a critical effector of the mTORC1-S6K1 signaling pathway in both adipocytes and macrophages, and contributes importantly to diet- induced obesity and atherosclerosis. Our discovery that EPRS is a key mTORC1-S6K1 effector activated by agonists of both inflammation and metabolism provides a molecular link between these processes. We anticipate our studies will reveal new mechanisms underlying obesity and atherosclerosis, and can provide novel therapeutic targets for treatment of these related disorders.

项目3（P3）。tRNA合成酶在代谢和动脉粥样硬化中的非经典活性 Paul L.福克斯博士，项目负责人 项目总结/摘要 项目3的长期目标是了解非凡的tRNA合成酶的非经典功能， Glu-Pro tRNA合成酶或EPRS，在饮食诱导的肥胖症和随后的心血管疾病中， 特别是动脉粥样硬化。最近肥胖、胰岛素抵抗和心血管疾病的爆发性流行 疾病已经开始在美国成年人的健康寿命前所未有的下降，同样， 这是前所未有的经济负担。1942年，詹姆斯·尼尔（James Neel）提出了一种可能的遗传学原理， 选择导致这些病理的基因。他假设代谢途径是自然选择的， 在食物短缺期间有效地储存脂肪和碳水化合物;然而，相同的基因和途径 在今天的西方世界，在食物供应充足、热量丰富的时期，激酶 涉及哺乳动物雷帕霉素靶蛋白（mTORC 1）和核糖体蛋白S6激酶-1（S6 K1）的级联反应， 被认为是调节食物利用的关键代谢途径，并且从果蝇到人类都是保守的。 尽管进行了大量的研究，mTORC 1-S6 K1的关键下游效应子和随后的细胞机制 调节新陈代谢的基因仍然未知。在上一个项目期间，我们在体外进行了基础研究， 以及体内发现显示磷酸化EPRS是mTORC 1-S6 K1的关键下游效应子， 调节巨噬细胞中的转录后炎症相关途径和 脂肪细胞肥胖者脂肪组织中炎性巨噬细胞浸润较多的脂肪细胞 受试者，并且在两种细胞类型中通过S6 K1的EPRS磷酸化可能在功能上偶联这些细胞，并且 对肥胖相关的心血管疾病有重要作用。为了测试磷酸化EPRS在这些中的作用， 我们已经产生了基因修饰的EPRS磷酸缺陷和磷酸模拟敲入过程 小鼠初步研究表明，磷酸缺陷型EPRS小鼠与S6 K1缺失型小鼠表型相似，例如，体积小 和低脂肪量，并将允许严格调查EPRS在mTORC 1-S6 K1驱动的 体内机制我们建议检验以下假设：磷酸化EPRS是该蛋白的关键效应子。 脂肪细胞和巨噬细胞中的mTORC 1-S6 K1信号通路，并对饮食- 诱发肥胖和动脉粥样硬化。我们发现EPRS是一个关键的mTORC 1-S6 K1效应子， 炎症和代谢两者的激动剂提供了这些过程之间的分子联系。我们 预计我们的研究将揭示肥胖和动脉粥样硬化的新机制， 用于治疗这些相关疾病的新的治疗靶点。