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Mitochondrial fusion protein MFN2 prevents platelet death and dysfunction

线粒体融合蛋白 MFN2 可预防血小板死亡和功能障碍

基本信息

批准号：
10308677
负责人：
JESSE ROWLEY
金额：
$ 38.13万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308677
关键词：
Affect Apoptosis Biological Assay Blood Platelets Blood coagulation Blood flow Cardiovascular Diseases Cardiovascular system Cells Cessation of life Chimeric Proteins Coagulation Process Data Development Developmental Process Disease Ensure Equilibrium Functional disorder Genetic Transcription Genetic study Goals Health Hemorrhage Hemostatic function Heterozygote Human Impairment In Vitro Inherited Knock-out Knockout Mice Lead Maintenance Mediating Megakaryocytes Metabolic Metabolic stress Methods Mitochondria Morphology Mus Myocardial Infarction Pathway interactions Phenotype Platelet Count measurement Production Proteins Pulmonary Embolism RNA Research Personnel Role Stroke Testing Thrombosis Time Transcript Transfusion Variant Work aged design genetic variant genome wide association study human data improved in vivo in vivo Model innovation insight mitochondrial dysfunction novel novel strategies platelet function preservation prevent therapeutic target transfusion medicine

项目摘要

Abstract Mitochondrial dysfunction is associated with numerous diseases, including disorders of thrombosis and hemostasis. Platelets inherit fully functional mitochondria from megakaryocytes, yet how megakaryocytes maintain mitochondrial integrity and function during their unique developmental process is unknown. Genetic studies have associated the mitochondrial maintenance and fusion protein Mitofusin 2 (MFN2) with platelet counts and cardiovascular disease. Our preliminary data show that loss of MFN2 in human platelets is associated with accelerated platelet death in vitro. Knockout of MNF2 in mice reduced platelet survival, and impaired hemostasis and thrombosis. Preliminary data suggest a mitochondrial role: loss of MFN2 disrupted mitochondrial morphology in megakaryocytes, and impaired mitochondrial function in platelets. In Aim 1 we test the hypothesis that MFN2 maintains mitochondrial integrity and function during megakaryocyte development to ensure platelets inherit fully functional and long-lived mitochondria. In Aim 2 we test the hypothesis that loss of MFN2 leads to platelet death, dysfunction, and altered hemostasis and thrombosis. Because MFN2 is especially important in adapting to metabolic stress, we will test each of these hypotheses under normal conditions and during metabolic stress. Each aim will have a mouse and human component: for mouse studies we will use platelet/megakaryocyte specific MFN2 knockouts, and for human studies we will utilize primary cells harboring a genetic variant that significantly reduces MFN2 expression in platelets. This work is significant because the results may lead to new approaches to target disorders of thrombosis and hemostasis, and improve platelet production and storage. This work is innovative: we will examine mitochondrial fusion, a novel pathway regulating platelet survival and function in health, during metabolic stress, and in transfused platelets. We will use innovative methods to examine mitochondrial function in new and circulatory aged platelets. Our studies will provide new insights into how MFN2 affects platelet death and dysfunction, an important step into understanding why human MFN2 variants are associated with platelet counts and cardiovascular disease.

摘要线粒体功能障碍与许多疾病相关，包括血栓形成和血栓形成障碍。止血。血小板从巨核细胞继承了功能齐全的线粒体，但巨核细胞如何在其独特的发育过程中维持线粒体的完整性和功能是未知的。遗传研究已经将线粒体维持和融合蛋白Mitofusin 2（MFN 2）与血小板聚集相关。计数和心血管疾病。我们的初步数据显示，人血小板中MFN 2的丢失是与体外血小板加速死亡有关。小鼠中MNF 2的敲除降低了血小板存活率，止血和血栓形成受损。初步数据表明线粒体的作用：MFN 2的丢失被破坏巨核细胞中的线粒体形态，以及血小板中受损的线粒体功能。在目的1中，我们检验了MFN 2在细胞凋亡过程中维持线粒体完整性和功能的假设。巨核细胞发育，以确保血小板继承功能齐全和寿命长的线粒体。在目标2 我们检验了MFN 2缺失导致血小板死亡、功能障碍和止血改变的假设，血栓形成由于MFN 2在适应代谢应激方面特别重要，我们将对这些基因进行检测。假设在正常条件下和代谢应激期间。每个目标将有一个鼠标和人组分：对于小鼠研究，我们将使用血小板/巨核细胞特异性MFN 2敲除，对于人研究，我们将使用血小板/巨核细胞特异性MFN 2敲除。研究中，我们将利用携带基因变异的原代细胞，该基因变异显著降低了MFN 2的表达。血小板这项工作是有意义的，因为结果可能导致新的方法来靶向血栓形成疾病和止血，并改善血小板的产生和储存。这项工作是创新的：我们将研究线粒体融合，一种调节健康血小板存活和功能的新途径，压力和输注的血小板。我们将使用创新的方法来检查线粒体功能，和循环老化的血小板。我们的研究将为MFN 2如何影响血小板死亡提供新的见解，功能障碍，理解为什么人类MFN 2变体与血小板相关的重要一步计数和心血管疾病。