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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：
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
项目类别：
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

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.

项目总结/文摘