Role of the mitochondrial fusion protein optic atrophy (OPA)-1 in platelet hyperactivity and thrombosis

 描述(由申请人提供)：心血管疾病(CVD)是美国主要的死亡原因(疾病控制中心)。血栓形成是心血管疾病最常见的潜在病理之一。糖尿病患者更容易患心血管疾病，心血管疾病是这些人死亡的主要原因；糖尿病患者发生血小板功能障碍的机制尚不完全清楚。初步研究结果显示，饮食诱导的肥胖小鼠线粒体动力学蛋白MFN-2、视神经萎缩(OPA)-1、动力蛋白相关蛋白(DRP)-1和线粒体裂变1蛋白(FIS1)的转录产物丰富；提示糖尿病环境中的血小板功能障碍可能与血小板线粒体动力学异常有关。因此，为了确定线粒体动力学和血小板功能障碍/血栓形成之间的关系，我们对调节线粒体动力学的蛋白质进行了血小板特异性缺失。这项提案将侧重于线粒体融合蛋白视神经萎缩(OPA)-1的作用。因此，将评估OPA-1缺失对导致不同配体激活血小板的信号通路的影响。我们的中心假设是，线粒体动力学和线粒体功能障碍的改变将通过增加氧化应激和随后的血小板过度活动来加速血栓形成的发展，部分原因是通过促进MPTP的开放。我们期望OPA-1缺乏的血小板的线粒体变化将反映高脂肪喂养的胰岛素抵抗小鼠糖尿病环境的变化。线粒体动力学对线粒体健康至关重要 这可能是糖尿病患者血栓形成增加的一个潜在机制。这一机制的验证将为血栓形成的病理生理学提供重要的洞察力，特别是在糖尿病患者中，糖尿病患者是心血管并发症的高危人群，如心肌和严重肢体缺血和脑中风。

 DESCRIPTION (provided by applicant): Cardiovascular diseases (CVD) are the leading cause of death in the United States (Center for Disease Control). Thrombosis represents one of the most common underlying pathologies in CVD. Diabetics are more susceptible to CVD, which is the leading cause of death in these individuals; the mechanisms by which platelet dysfunction develops in diabetics are incompletely understood. Preliminary findings revealed enrichment in transcripts encoding the mitochondrial dynamics proteins mitofusin (MFN)-2, optic atrophy (OPA)-1, dynamin-related protein (DRP)-1, and mitochondrial fission 1 protein (FIS1) in diet-induced obese mice; suggesting that platelet dysfunction in the diabetic milieu might be related to abnormal mitochondrial dynamics in platelets. Thus, in an effort to define the relationship between mitochondrial dynamics and platelet dysfunction/thrombosis we performed platelet-specific deletion of proteins that regulate mitochondrial dynamics. This proposal will focus on the role of the mitochondrial fusion protein Optic Atrophy (OPA)-1. Thus, the effects of OPA-1 deletion on the signaling pathways leading to platelet activation by various ligands will be evaluated. Our central hypothesis is that changes in mitochondrial dynamics and mitochondrial dysfunction will accelerate the development of thrombosis by increasing oxidative stress and subsequent platelet hyperactivity, in part, by promoting MPTP opening. We expect that the mitochondrial changes in OPA-1 deficient platelets will mirror the changes in the diabetic milieu of high fat fed insulin resistant mice. Mitochondrial dynamics is critical for mitochondrial health and may be one underlying mechanism for increased thrombosis in diabetics. Validation of this mechanism would provide critical insight into the pathophysiology of thrombosis, particularly in diabetics which represent an at risk population for cardiovascular complications such as myocardial and critical limb ischemia and cerebral strokes