Platelet Mitochondrial Function in Health and Disease

描述（申请人提供）：血小板在血栓形成的复杂过程中起着至关重要的作用。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凋亡的许多主要组成部分（例如DNA损伤和断裂）和对凋亡的反应。我们和其他人最近证实了糖尿病（DM）中血小板凋亡导致血栓增加。对于日益增长的糖尿病患者，迫切需要发现新的机制，并开发新的治疗方法，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，证明线粒体功能障碍和凋亡在糖尿病血小板。此外，一种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烯酸（花生四烯酸代谢物）也可能保护糖尿病血小板免于凋亡和血栓形成。根据我们的初步结果，我们假设由高血糖引起的血小板线粒体功能障碍导致血小板凋亡和血栓形成增加。通过三个特定目标，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（Specific Aim #1）。我们将进一步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（Specific Aim #2）。特异性目的#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患者的线粒体功能障碍和细胞凋亡。我们在血小板生物学，线粒体生物学和细胞凋亡领域的国际知名专家团队将在短期内破译糖尿病线粒体功能障碍和细胞凋亡调节的重要新机制。从长远来看，我们将找到新的靶点来治疗血小板介导的血栓形成。

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.