Platelet mitochondrial function in health and disease

血小板线粒体在健康和疾病中的功能

• 批准号: 9884665
• 负责人: JOHN HWA
• 金额: $ 50.58万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884665
• 关键词: Address; Amino Acids; Antioxidants; Apoptosis; Apoptotic; Area; Attenuated; Back; Biochemical; Biochemical Process; Biological; Biological Process; Biology; Blood Circulation; Blood Platelets; Blood Vessels; Cardiovascular system; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Data; Defect; Diabetes Mellitus; Diagnosis; Disease; Doctor of Medicine; Doctor of Philosophy; Dose; Economics; Enzymes; Essential Fatty Acids; Event; Fatty Acids; Functional disorder; Goals; Health; Hyperglycemia; Hypoglycemia; International; Investigation; Lead; Link; Lipids; Mediating; Metabolic; Metabolic dysfunction; Metabolism; Methionine; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Modification; Molecular; Morbidity - disease rate; Myocardial Infarction; Obesity; Oxidative Stress; Oxides; Oxygen; Patients; Play; Population; Post-Translational Protein Processing; Prevalence; Process; Proteins; Proteomics; Regulation; Reporting; Role; Signal Transduction; Source; Stroke; Testing; Therapeutic; Thrombosis; Universities; base; diabetic; diabetic patient; effective therapy; fatty acid metabolism; insight; lipid metabolism; long chain fatty acid; metabolomics; methionine sulfoxide reductase; mitochondrial dysfunction; mitochondrial metabolism; mortality; new therapeutic target; novel; oxidation; parkin gene/protein; prevent; recruit; response; statistics; therapeutic target

PROJECT SUMMARY/ABSTRACT With the increasing prevalence of obesity in the USA, diabetes mellitus is a growing concern. Most diabetic patients will die from a thrombotic vascular event (heart attack or stroke) where the effects of oxidative stress on platelets, arising from major metabolic disturbances such has hyperglycemia, play a major role. How oxidative stress directly leads to platelet dysfunction is currently an intense area of investigation. We have recently performed rigorous proteomic and metabolomic profiling in diabetic versus healthy platelets and identified specific oxidized methionine modifications in key mitochondrial metabolic proteins, that may be the source for some of the major cellular metabolic disturbances (defects in mitophagy and lipid beta- oxidation) associated with diabetic platelets. Moreover, MsrB2, an understudied mitochondrial matrix enzyme, can reverse these oxidative-stress induced methionine oxidative changes, protecting platelets. Based upon our Preliminary Studies we hypothesize that DM associated oxidative stress modifies key proteins involved in essential cellular biological and biochemical processes; mitochondria specific MsrB2 may play a critical role in reversing such potentially harmful changes, thus protecting DM patients from thrombovascular events. In addressing our hypothesis, we present three Specific Aims. Specific Aim #1 will be to assess the effects of oxidative stress on Parkin and the recently described platelet mitophagy protective process. Specific Aim #2 will be to determine whether methionine modification of HADHA, a key component of the mitochondrial trifunctional protein, perturbs mitochondrial beta-oxidation. The third Specific Aim addresses whether MsrB2 plays a role in rectifying these disturbances, in addition to possible other anti-oxidant avenues for therapy. Our team of internationally recognized experts in the areas of diabetes mellitus, platelet biology, mitochondrial biology and metabolism, will in the short term decipher important new mechanisms regulating mitochondrial dysfunction and apoptosis in diabetes mellitus. In the long term, we will have identified new targets for novel therapy against platelet mediated adverse cardiovascular events in diabetes mellitus.

项目总结/摘要 随着肥胖症在美国的日益流行，糖尿病日益受到关注。大多数糖尿病 患者将死于血栓性血管事件（心脏病发作或中风），其中氧化作用 由主要代谢紊乱如高血糖症引起的对血小板的应激起主要作用。 氧化应激如何直接导致血小板功能障碍是目前研究的热点。我们 最近对糖尿病患者与健康血小板进行了严格的蛋白质组学和代谢组学分析 并在关键的线粒体代谢蛋白中鉴定了特定的氧化甲硫氨酸修饰， 是一些主要的细胞代谢紊乱（线粒体自噬和脂质β- 氧化）与糖尿病血小板相关。此外，研究不足的线粒体基质MsrB 2 酶，可以逆转这些氧化应激诱导的蛋氨酸氧化变化，保护血小板。 基于我们的初步研究，我们假设糖尿病相关的氧化应激改变了关键的 参与基本细胞生物学和生物化学过程的蛋白质类;线粒体特异性MsrB 2 可能在逆转这些潜在的有害变化方面发挥关键作用，从而保护DM患者免受 血栓事件。在讨论我们的假设时，我们提出了三个具体目标。具体目标#1 评估氧化应激对帕金和最近描述的血小板线粒体自噬的影响， 保护过程。具体目标#2将是确定HADHA的甲硫氨酸修饰， 线粒体三功能蛋白的组成部分，干扰线粒体β-氧化。第三 具体目标解决了MsrB 2是否在纠正这些干扰中发挥作用，除了可能的 其他抗氧化剂的治疗途径。我们的团队由国际公认的专家组成， 糖尿病，血小板生物学，线粒体生物学和代谢，将在短期内破译 糖尿病中调节线粒体功能障碍和细胞凋亡的重要新机制。在 从长远来看，我们将确定新的靶点，用于治疗血小板介导的不良反应。 糖尿病的心血管事件。