Platelet mitochondrial function in health and disease
血小板线粒体在健康和疾病中的功能
基本信息
- 批准号:10600123
- 负责人:
- 金额:$ 50.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAmino AcidsAntioxidantsApoptosisApoptoticAreaAspirinAttenuatedBackBiochemicalBiochemical ProcessBiologicalBiological ProcessBiologyBlood PlateletsBlood VesselsCardiovascular systemCell physiologyCellsCirculationDataDefectDiabetes MellitusDiagnosisDiseaseDoctor of MedicineDoctor of PhilosophyDoseEconomicsEnzymesEssential Fatty AcidsEventFatty AcidsFunctional disorderGoalsHealthHyperglycemiaHypoglycemiaInternationalInvestigationLinkLipidsMediatingMetabolicMetabolic dysfunctionMetabolismMethionineMitochondriaMitochondrial MatrixMitochondrial ProteinsModelingModificationMolecularMorbidity - disease rateMyocardial InfarctionObesityOxidative StressOxidative Stress InductionOxygenParkinPatientsPlayPopulationPost-Translational Protein ProcessingPrevalenceProcessProteinsProteomicsRegulationReportingRoleSignal TransductionSourceStrokeTestingTherapeuticThrombosisUniversitiesdiabeticdiabetic patienteffective therapyfatty acid metabolisminsightlipid metabolismlong chain fatty acidmetabolomicsmethionine sulfoxide reductasemitochondrial dysfunctionmitochondrial metabolismmortalitynew therapeutic targetnoveloxidationpreventrecruitresponsestatisticstherapeutic targetthrombotic
项目摘要
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.
项目概要/摘要
随着美国肥胖症患病率的不断上升,糖尿病越来越受到人们的关注。大多数糖尿病患者
患者将死于血栓性血管事件(心脏病发作或中风),其中氧化作用的影响
由高血糖等主要代谢紊乱引起的血小板压力起着重要作用。
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领域。我们
最近对糖尿病与健康血小板进行了严格的蛋白质组学和代谢组学分析
并确定了关键线粒体代谢蛋白中特定的氧化蛋氨酸修饰,这可能
是一些主要细胞代谢紊乱(线粒体自噬和脂质β-缺陷)的根源
氧化)与糖尿病血小板有关。此外,MsrB2,一种正在研究的线粒体基质
酶,可以逆转这些氧化应激引起的蛋氨酸氧化变化,保护血小板。
根据我们的初步研究,我们假设 DM 相关的氧化应激改变了关键
参与重要细胞生物学和生化过程的蛋白质;线粒体特异性 MsrB2
可能在扭转这种潜在有害变化方面发挥关键作用,从而保护糖尿病患者免受
血栓血管事件。在解决我们的假设时,我们提出了三个具体目标。具体目标#1 将
评估氧化应激对 Parkin 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 是确定 HADHA 是否受到蛋氨酸修饰,这是一个关键
线粒体三功能蛋白的组成部分,扰乱线粒体β-氧化。第三个
具体目标除了可能的解决方案之外,还解决了 MsrB2 是否在纠正这些干扰方面发挥作用。
其他抗氧化治疗途径。我们的团队由以下领域的国际公认专家组成
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
调节糖尿病线粒体功能障碍和细胞凋亡的重要新机制。在
从长远来看,我们将确定针对血小板介导的不良反应的新疗法的新靶点
糖尿病中的心血管事件。
项目成果
期刊论文数量(17)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Unfolded Protein Response Differentially Modulates the Platelet Phenotype.
- DOI:10.1161/circresaha.121.320530
- 发表时间:2022-08-05
- 期刊:
- 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
Regulation of VWF expression, and secretion in health and disease.
- DOI:10.1097/moh.0000000000000230
- 发表时间:2016-05
- 期刊:
- 影响因子:3.2
- 作者:Xiang Y;Hwa J
- 通讯作者:Hwa J
Insights into platelet pharmacology from a cryo-EM structure of the ABCC4 transporter.
从 ABCC4 转运蛋白的冷冻电镜结构深入了解血小板药理学。
- DOI:10.1038/s44161-023-00293-z
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Sharda,AnishV;Gu,SeanX;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:
- 影响因子:0
- 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:
- 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
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JOHN HWA其他文献
JOHN HWA的其他文献
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{{ truncateString('JOHN HWA', 18)}}的其他基金
Yale Cooperative Center of Excellence in Hematology
耶鲁大学血液学卓越合作中心
- 批准号:
10677840 - 财政年份:2015
- 资助金额:
$ 50.58万 - 项目类别:
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 - 财政年份:2015
- 资助金额:
$ 50.58万 - 项目类别:
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:
10088457 - 财政年份:2015
- 资助金额:
$ 50.58万 - 项目类别:
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:
8817070 - 财政年份:2015
- 资助金额:
$ 50.58万 - 项目类别:
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:
10390280 - 财政年份:2015
- 资助金额:
$ 50.58万 - 项目类别:
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:
9243286 - 财政年份:2015
- 资助金额:
$ 50.58万 - 项目类别:
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:
9041675 - 财政年份:2015
- 资助金额:
$ 50.58万 - 项目类别:
Hyperglycemia, thromboxane and platelet activity in diabetes mellitus
糖尿病中的高血糖、血栓素和血小板活性
- 批准号:
8344530 - 财政年份:2012
- 资助金额:
$ 50.58万 - 项目类别:
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