The Effects of a Novel Statin-Induced Protein Modification on Fatty Acid Synthase

新型他汀类药物诱导的蛋白质修饰对脂肪酸合酶的影响

• 批准号: 9766354
• 负责人: Alec Trub
• 金额: $ 3.6万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2020-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766354
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Active Sites; Affect; Arteries; Biological Assay; Blood; Carbon; Cardiovascular Diseases; Cell Culture Techniques; Cells; Cholesterol; Cholesterol Homeostasis; Coenzyme A; Communication; Data; Diabetes Mellitus; Drug Prescriptions; Enzymes; Fatty Acids; Fatty-acid synthase; Future; Gene Expression; Goals; Health; Heart Diseases; Hematological Disease; In Vitro; Individual; Knowledge; Label; Lead; Link; Lipids; Location; Lung diseases; Mass Spectrum Analysis; Measures; Mediating; Metabolism; Mission; Modification; Muscle; Muscle function; Myopathy; National Heart, Lung, and Blood Institute; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Post-Translational Protein Processing; Prevention; Production; Proteins; Public Health; Research; Risk; Role; Site; Smooth Muscle; Stream; Structure; Testing; Tissues; Toxic effect; United States National Institutes of Health; Work; animal tissue; base; cardiovascular disorder prevention; cardiovascular disorder therapy; cholesterol biosynthesis; disorder prevention; fatty acid metabolism; improved; in vitro activity; lipid biosynthesis; lipid metabolism; novel; personalized medicine; platelet function; pleiotropism; prevent; protein function; response; side effect; uptake

Statins are among the most widely prescribed drugs in the world because of their effective prevention of cardiovascular disease; however, the mechanism and effects of statins are incompletely understood. Recent work in our lab has identified a novel post-translational modification in response to statin treatment on fatty acid synthase (FASN). The long-term goal is to understand changes in cellular metabolism that occur during statin therapy and how they contribute to the drug’s pleiotropic effects. The objective of this proposal is to determine how the novel protein modification affects FASN. The central hypothesis is that statin-induced modification of fatty acid synthase modulates fatty acid metabolism during statin therapy. This is based on preliminary data that suggests that active site residues of fatty acid synthase are modified and can inhibit FASN. The rational for the proposed research is that understanding statin effects on fatty acid metabolism may provide a mechanistic explanation for statin therapy side effects that may be manipulated to improve treatment and patient health. Based on preliminary data, the central hypothesis will be tested by pursuing two specific aims: 1) identify the site(s) of the statin-induced modification on fatty acid synthase, and 2) Determine the effects of statins on fatty acid synthase activity. In the first aim, mass spectrometry will accurately identify sites of modification on FASN labeled in vitro, as well as FASN extracted from statin treated cells. In the second aim, in vitro activity assays will be conducted on purified FASN, to examine how activity changes in the presence of the modification. Additionally, labeled carbon tracing studies in cells will be used to measure changes in fatty acid production in the context of statin treatment. The results are expected to have a significant impact by elucidating the effects of a previously unknown modification caused by statin therapy. This will improve the ability to understand and manage the side effects caused by statin therapy, furthering the mission of the NHLBI to “promote the prevention and treatment of heart, lung, and blood diseases and enhance the health of all individuals so that they can live longer and more fulfilling lives.”

他汀类药物是世界上最广泛的处方药之一，因为它们的有效 预防心血管疾病;然而，他汀类药物的机制和作用是 不完全理解。我们实验室最近的工作发现了一种新的翻译后 对他汀类药物治疗的反应对脂肪酸合成酶（FATCH）的修饰。远景目标 是了解他汀类药物治疗期间细胞代谢的变化，以及它们是如何 有助于药物的多效性。本提案的目的是确定 新的蛋白质修饰影响了FEV 1。中心假设是他汀类药物诱导的 脂肪酸合成酶的修饰在他汀治疗期间调节脂肪酸代谢。这是 基于初步的数据表明脂肪酸合酶的活性位点残基是 改性并能抑制FEV 1。提出这项研究的理由是， 他汀类药物对脂肪酸代谢的影响可能为他汀类药物治疗提供了机制解释 副作用，可以操纵，以改善治疗和病人的健康。基于 初步数据，中心假设将通过追求两个具体目标进行测试：1）识别 他汀类药物诱导的脂肪酸合成酶修饰的位点，和2）确定影响 对脂肪酸合成酶活性的影响。在第一个目标中，质谱法将准确地 鉴定体外标记的以及从他汀类药物提取的FcR上的修饰位点 处理的细胞。在第二个目标中，将对纯化的FASN进行体外活性测定， 检查在存在修饰的情况下活性如何变化。此外，标记碳 在细胞中的跟踪研究将被用来测量脂肪酸生产的变化， 他汀治疗。预计这些结果将通过阐明这些效应产生重大影响 他汀类药物治疗引起的一种以前未知的改变。这将提高能力， 了解和管理他汀类药物治疗引起的副作用，进一步推进他汀类药物的使命， NHLBI旨在“促进心脏、肺和血液疾病的预防和治疗， 增强所有人的健康，使他们能够活得更长，更充实。”