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: 10600123
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600123
• 关键词: Address; Amino Acids; Antioxidants; Apoptosis; Apoptotic; Area; Aspirin; Attenuated; Back; Biochemical; Biochemical Process; Biological; Biological Process; Biology; Blood Platelets; Blood Vessels; Cardiovascular system; Cell physiology; Cells; Circulation; 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; Link; Lipids; Mediating; Metabolic; Metabolic dysfunction; Metabolism; Methionine; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Modification; Molecular; Morbidity - disease rate; Myocardial Infarction; Obesity; Oxidative Stress; Oxidative Stress Induction; Oxygen; Parkin; Patients; Play; Population; Post-Translational Protein Processing; Prevalence; Process; Proteins; Proteomics; Regulation; Reporting; Role; Signal Transduction; Source; Stroke; Testing; Therapeutic; Thrombosis; Universities; 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; prevent; recruit; response; statistics; therapeutic target; thrombotic

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.

项目摘要/摘要 随着肥胖症在美国的越来越多，糖尿病是越来越关注的问题。最糖尿病 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 由于主要的代谢障碍引起的血小板压力具有高血糖，起着主要作用。 目前，氧化应激如何直接导致血小板功能障碍是一个强烈的研究领域。我们 最近在糖尿病与健康血小板中进行了严格的蛋白质组学和代谢组分析 并确定了关键线粒体代谢蛋白中的特定氧化蛋氨酸修饰，这可能 成为一些主要的细胞代谢障碍的来源（线粒体和脂质β-缺陷 氧化）与糖尿病血小板有关。此外，MSRB2，一个研究的线粒体矩阵 酶，可以扭转这些氧化压力诱导的蛋氨酸氧化变化，从而保护血小板。 基于我们的初步研究，我们假设DM相关的氧化应激修饰了关键 参与必需细胞生物学和生化过程的蛋白质；线粒体特异性MSRB2 可能在逆转这种潜在有害变化中起关键作用，从而保护DM患者免受 血小板事件。在解决我们的假设时，我们提出了三个具体目标。特定的目标＃1将 要评估氧化应激对Parkin和最近描述的血小板线粒体的影响 保护过程。具体目标＃2将是确定甲硫氨酸的修改哈达是否是钥匙 线粒体三官能蛋白的成分，即线粒体β-氧化。第三 具体目的解决了MSRB2是否在纠正这些干扰中起作用，此外 其他抗氧化剂治疗途径。我们在国际公认的专家团队 糖尿病，血小板生物学，线粒体生物学和代谢，将在短期破译中 调节糖尿病中线粒体功能障碍和凋亡的重要新机制。在 长期，我们将确定针对血小板介导的不良疗法的新靶标 糖尿病中的心血管事件。

项目成果

Unfolded Protein Response Differentially Modulates the Platelet Phenotype.

• DOI: 10.1161/circresaha.121.320530
• 发表时间: 2022-08-05
• 期刊: CIRCULATION RESEARCH
• 影响因子: 20.1
• 作者: Jain, Kanika;Tyagi, Tarun;Du, Jing;Hu, Xiaoyue;Patell, Kanchi;Martin, Kathleen A.;Hwa, John
• 通讯作者: Hwa, John

Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response.

• DOI: 10.1161/atvbaha.117.310053
• 发表时间: 2017-12
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Jin Y;Xie Y;Ostriker AC;Zhang X;Liu R;Lee MY;Leslie KL;Tang W;Du J;Lee SH;Wang Y;Sessa WC;Hwa J;Yu J;Martin KA
• 通讯作者: Martin KA

Technical Feasibility of a Murine Model of Sleeve Gastrectomy with Ileal Transposition.

回肠转位袖状胃切除术小鼠模型的技术可行性。

• DOI: 10.1007/s11695-018-3555-7
• 发表时间: 2019
• 期刊: Obesity surgery
• 影响因子: 2.9
• 作者: Ying,LeeD;Breuer,GregoryA;Hubbard,MatthewO;Nadzam,GeoffreyS;Hwa,John;Martin,KathleenA
• 通讯作者: Martin,KathleenA

Molecular Imaging of Factor XIII Activity for the Early Detection of Mouse Coronary Microvascular Disease.

因子 XIII 活性的分子成像用于早期检测小鼠冠状动脉微血管疾病。

• DOI: 10.7150/thno.29255
• 发表时间: 2019
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Zhuang,ZhenW;Huang,Yang;Ju,Rong;Maxfield,MarkW;Ren,Yongming;Wang,Xiangning;Wang,Xinlu;Stacy,MitchelR;Hwa,John
• 通讯作者: Hwa,John

Regulation of VWF expression, and secretion in health and disease.

• DOI: 10.1097/moh.0000000000000230
• 发表时间: 2016-05
• 期刊: Current opinion in hematology
• 影响因子: 3.2
• 作者: Xiang Y;Hwa J
• 通讯作者: Hwa J