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：
8817070
负责人：
JOHN HWA
金额：
$ 41.63万
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 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8817070
关键词：
Acids Acute Address Adult Antiplatelet Drugs Apoptosis Apoptotic Arachidonic Acids Area Aspirin Biology Blood Platelets Cardiovascular system Cell Nucleus Cells Cessation of life Chronic Complex DNA DNA Damage DNA Fragmentation Data Diabetes Mellitus Diagnosis Digestion Disease Distal Drug usage Electron Microscopy Event Fatty Acids Functional disorder Glucose Goals Health Human Hyperglycemia Lead Literature MAPK8 gene Mediating Membrane Potentials Mitochondria Mitogens Modeling Morbidity - disease rate Mus Myocardial Infarction Obesity Overweight Pathway interactions Patients Phosphorylation Play Population Process Production Prostaglandins I Proteins Proteomics Reporting Resistance Role Signal Transduction Stroke Technology Testing Therapeutic Thrombosis Thrombus Time arachidonate atherothrombosis base diabetic diabetic patient effective therapy mitochondrial dysfunction mitochondrial membrane mortality novel novel therapeutic intervention novel therapeutics oxidation premature prevent protein profiling public health relevance repaired response single cell analysis targeted treatment therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Platelets play an essential role in the complex process of thrombus formation. Disruption of mitochondrial membrane and its membrane potential, can lead to inefficient ATP production, excessive ROS production, oxidation of protein, and fatty acids, and subsequent apoptosis. Interestingly, platelets do not have a nucleus to mediate many of the major components of apoptosis (e.g. DNA damage and fragmentation) and response to apoptosis. We and others have recently demonstrated platelet apoptosis in diabetes mellitus (DM) leading to increased thrombosis. There is an urgent need identify new mechanisms, and develop new therapies, to target platelet apoptosis and thrombosis, for the growing population of diabetic patients. We now present new preliminary results demonstrating mitochondrial dysfunction and apoptosis in diabetic platelets. Moreover activation of a novel mitophagy process appears to protect the platelet from apoptosis. Additionally, prostacyclin and epoxyeicosaenoic acid (arachidonic acid metabolites) may also protect diabetic platelets from apoptosis and thrombosis. Based on our Preliminary Results we hypothesize that mitochondrial dysfunction in platelets, arising from hyperglycemia, leads to platelet apoptosis and increased thrombosis. Through three Specific Aims we will decipher the mechanism by which hyperglycemia induces platelet mitochondrial dysfunction and assess pathways distal to platelet mitochondrial dysfunction leading to apoptosis (Specific Aim #1). We will additionally study the process of mitophagy, and how this impacts platelet mitochondrial function and apoptosis (Specific Aim #2). Specific Aim #3 will determine whether epoxyeicosaenoic acid and prostacyclin, two potentially novel therapeutic approaches, can protect against mitochondrial dysfunction and apoptosis in diabetes mellitus. Our team of internationally recognized experts in the areas of platelet biology, mitochondrial biology and apoptosis 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 thrombosis.

描述（由申请人提供）：血小板在血栓形成的复杂过程中发挥着重要作用。线粒体膜及其膜电位的破坏可导致 ATP 产生效率低下、ROS 产生过多、蛋白质和脂肪酸氧化以及随后的细胞凋亡。有趣的是，血小板没有细胞核来介导细胞凋亡的许多主要成分（例如 DNA 损伤和断裂）和细胞凋亡反应。我们和其他人最近证明糖尿病（DM）中的血小板凋亡会导致血栓形成增加。对于不断增长的糖尿病患者群体，迫切需要确定新机制并开发新疗法，以针对血小板凋亡和血栓形成。我们现在提出新的初步结果，证明糖尿病血小板中的线粒体功能障碍和细胞凋亡。此外，新的线粒体自噬过程的激活似乎可以保护血小板免于凋亡。此外，前列环素和环氧二十碳烯酸（花生四烯酸代谢物）也可以保护糖尿病血小板免于细胞凋亡和血栓形成。根据我们的初步结果，我们假设高血糖引起的血小板线粒体功能障碍会导致血小板凋亡和血栓形成增加。通过三个具体目标，我们将破译高血糖诱导血小板线粒体功能障碍的机制，并评估血小板线粒体功能障碍导致细胞凋亡的远端途径（具体目标#1）。我们还将研究线粒体自噬的过程，以及它如何影响血小板线粒体功能和细胞凋亡（具体目标#2）。具体目标#3将确定环氧二十碳烯酸和前列环素这两种潜在的新型治疗方法是否可以预防糖尿病中的线粒体功能障碍和细胞凋亡。我们的血小板生物学、线粒体生物学和细胞凋亡领域国际公认的专家团队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。从长远来看，我们将确定针对血小板介导的血栓形成的新疗法的新靶点。