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

线粒体融合蛋白视神经萎缩（OPA）-1在血小板过度活跃和血栓形成中的作用

基本信息

批准号：
9145489
负责人：
Rhonda Andrea Souvenir
金额：
$ 4.72万
依托单位：
UNIVERSITY OF IOWA
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：
2015-09-16 至 2017-06-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9145489
关键词：
Abnormal Platelet Agonist Antioxidants Biological Markers Blood Platelets Blood Vessels Blood coagulation Cardiovascular Diseases Cardiovascular system Cause of Death Centers for Disease Control and Prevention (U.S.)Chimeric Proteins Data Development Diabetes Mellitus Diet Dynamin I Exhibits Fatty acid glycerol esters Functional disorder Gene Expression Gene Targeting Genes Glycoproteins Goals Health High Fat Diet Hyperactive behavior In Vitro Individual Insulin Resistance Integrins Ischemia Knockout Mice Laboratories Ligands Limb structure Link Membrane Potentials Metabolic syndrome Mitochondria Mitochondrial Proteins Molecular Morbidity - disease rate Mus Myocardial NADPH Oxidase Obese Mice Obesity Optic Atrophy Outcome Oxidative Stress Pathology Phenotype Platelet Activation Platelet Count measurement Population Populations at Risk Protein Dynamics Proteins Research Risk Role Secondary Prevention Signal Pathway Stroke Testing Thrombosis Thromboxane A2 Receptor Thrombus Transcript Validation Venous convulxin diabetic feeding high risk in vivo insight mitochondrial dysfunction mitochondrial membrane mitochondrial permeability transition pore mortality novel strategies receptor response stroke therapy

项目摘要

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

描述（由申请人提供）：心血管疾病（CVD）是美国（疾病控制中心）的主要死亡原因。血栓形成是CVD中最常见的基础病理之一。糖尿病患者更容易患CVD，这是这些个体死亡的主要原因;糖尿病患者血小板功能障碍的机制尚未完全了解。初步研究结果显示，在饮食诱导的肥胖小鼠中，编码线粒体动力学蛋白线粒体融合蛋白（MFN）-2，视神经萎缩（OPA）-1，dynamin-related protein（DRP）-1和mitochondrial fission 1 protein（FIS 1）的转录物富集;这表明糖尿病环境中的血小板功能障碍可能与血小板中的异常线粒体动力学有关。因此，为了确定线粒体动力学与血小板功能障碍/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。这项提案将集中在线粒体融合蛋白视神经萎缩（OPA）-1的作用。因此，将评估OPA-1缺失对导致各种配体激活血小板的信号传导途径的影响。我们的中心假设是，线粒体动力学和线粒体功能障碍的变化将加速血栓形成的发展，增加氧化应激和随后的血小板过度活跃，在一定程度上，通过促进MPTP开放。我们预期OPA-1缺陷型血小板中线粒体的变化将反映高脂喂养的胰岛素抵抗小鼠的糖尿病环境的变化。线粒体动力学对线粒体健康至关重要并且可能是糖尿病患者中血栓形成增加的一种潜在机制。验证这一机制将为血栓形成的病理生理学提供重要见解，特别是在糖尿病患者中，糖尿病患者是心肌和严重肢体缺血和脑中风等心血管并发症的高危人群