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

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

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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.

抽象的线粒体功能障碍与许多疾病有关，包括血栓形成和止血。血小板从巨核细胞继承了功能完全实用的线粒体，但是巨核细胞的方式在其独特的发育过程中保持线粒体完整性和功能是未知的。遗传研究已将线粒体维持和融合蛋白丝线素2（MFN2）与血小板相关联计数和心血管疾病。我们的初步数据表明，人血小板中MFN2的损失是与体外加速血小板死亡有关。小鼠中MNF2的敲除可降低血小板的存活，而止血和血栓形成受损。初步数据表明线粒体角色：MFN2的丢失被破坏巨核细胞中的线粒体形态，血小板中的线粒体功能受损。在AIM 1中，我们检验了MFN2在保持线粒体完整性和功能期间的假设巨核细胞的发育确保血小板继承了完全功能和长寿的线粒体。在目标2中我们检验了MFN2丢失导致血小板死亡，功能障碍和止血改变和止血和改变的假设血栓形成。由于MFN2在适应代谢压力方面尤其重要，因此我们将测试其中的每一个假设在正常条件下和代谢应激期间。每个目标都会有鼠标和人类组成部分：对于鼠标研究，我们将使用血小板/巨核细胞特定的MFN2敲除，对于人类研究我们将利用具有遗传变异的主要细胞，可显着降低MFN2的表达血小板。这项工作很重要，因为结果可能会导致针对血栓形成障碍的新方法和止血，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是一种新型途径，调节血小板生存和健康功能，在代谢期间压力和输血的血小板。我们将使用创新方法检查新的线粒体功能和循环老化的血小板。我们的研究将为MFN2如何影响血小板死亡和功能障碍，了解为什么人MFN2变体与血小板相关的重要一步计数和心血管疾病。