The Biogenesis of Platelet-Derived Extracellular Vesicles and their Impact on Megakaryocyte Maturation
血小板源性细胞外囊泡的生物发生及其对巨核细胞成熟的影响
基本信息
- 批准号:10394422
- 负责人:
- 金额:$ 57.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-20 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAgonistBindingBiogenesisBiologyBlood PlateletsBone MarrowBone Marrow CellsCardiovascular DiseasesCell membraneCellsClinicalCollagenDataDependenceDevelopmentDiseaseEnvironmentFamilyGene ExpressionGenerationsGoalsHematopoieticHemorrhageHumanIn VitroInflammationInflammatoryKnowledgeLeadLifeLinkMediatingMegakaryocytesMegakaryocytopoiesesMembrane FusionMessenger RNAMicroRNAsModelingMonomeric GTP-Binding ProteinsMorbidity - disease rateMothersMusOutcome StudyPathogenicityPathologicPathway interactionsPatientsPlasmaPlatelet ActivationPlatelet Count measurementProductionPropertyRegulationResearchSignal TransductionSteroidsSystemic Lupus ErythematosusTherapeutic InterventionThrombinThrombocytopeniaThrombopoiesisThrombopoietinTimeTranscriptUp-Regulationblood productexperimental studyextracellular vesiclesin vivoinhibitorinsightmembermicrovesiclesmimeticsmortalitynew therapeutic targetnovelpreventresponserhorho GTP-Binding Proteinsside effectthrombocytosistranscription factortranscriptomeuptake
项目摘要
The Biogenesis of Platelet-Derived Extracellular Vesicles and their Impact on
Megakaryocyte Maturation
Abstract
Thrombocytopenia is a major clinical problem encountered in multiple conditions, and severe
thrombocytopenia (platelet counts <50 x 10^9/L) can lead to life threatening bleeding. Current treatment
options have severe side effects, are in limited supply, involve blood products, and the platelet response
typically takes up to 12 days. Therefore, there is an urgent need to identify new thrombopoietic agents that
increase platelet counts for patients. In many inflammatory conditions platelet counts rise, resulting in
thrombocytosis, but what initiates this platelet up-regulation is not well understood. Our lab uses inflammation
as a model of exacerbated thrombopoiesis that results in differences in platelet quality and quantity in order to
1) gain a better understanding of the basic biology of megakaryocyte (MK) maturation their production of
platelets, 2) identify thrombopoietin (TPO) independent pathways of MK maturation, and 3) determine ways to
reduce platelet-related morbidity and mortality in inflammation. We have discovered a novel regulator of MK
maturation during inflammation: platelet-derived extracellular vesicles (PEVs) in the bone marrow. Our
preliminary data indicate that platelets package and shed MVs in an agonist-specific mechanism dependent on
Rho GTPase signaling; the mechanism of Rho-mediated regulation of PEV formation and packaging will be
explored in Aim 1. We also found that PEVs enter the bone marrow from the plasma, and bind to and are
endocytosed by MKs both in vitro and in vivo. In Aim 2, we will examine how platelet-derived MVs interact with
MKs. Specifically, we will determine the mechanisms by which they bind to and are internalized by MKs and
how their cargo transferred. In inflammatory conditions such as SLE, ongoing platelet activation increases
levels of circulating PEVs. These PEVs deliver disease-related changes from the plasma milieu directly to MKs
in the bone marrow, reprogramming the MKs to make more pathogenic platelets. In Aim 3, we will identify the
PEV factors that alter MK gene expression and platelet content in SLE. Successful completion of the proposed
experiments will, for the first time, provide a detailed roadmap of how PEVs alter the hematopoietic
environment in the setting of inflammatory disease. The insights gained may identify novel therapeutic targets
that (i) alter PEV poduction independent of platelet activation (Aim 1), (ii) hijack the PEV/MK interaction to alter
MK maturation (Aim 2), and (iii) inhibit pathologic MK reprogramming during SLE and other inflammatory
diseases (Aim 3).
血小板源性细胞外囊泡的生物学发生及其对血小板功能的影响
巨核细胞成熟
摘要
血小板减少症是在多种情况下遇到的主要临床问题,并且严重
血小板减少症(血小板计数<50 x 10^9/L)可导致危及生命的出血。当前治疗
选择有严重的副作用,供应有限,涉及血液制品和血小板反应
通常需要长达12天。因此,迫切需要鉴定新的血小板生成剂,
增加患者的血小板计数。在许多炎症性疾病中,血小板计数升高,导致
血小板增多症,但什么启动这种血小板上调还没有很好地理解。我们的实验室用炎症
作为血小板生成恶化的模型,导致血小板质量和数量的差异,
1)更好地了解巨核细胞(MK)成熟的基础生物学,
血小板,2)鉴定MK成熟的血小板生成素(TPO)独立途径,和3)确定
降低炎症中血小板相关的发病率和死亡率。我们发现了一种新的MK调节剂
炎症期间的成熟:骨髓中血小板衍生的细胞外囊泡(PEV)。我们
初步数据表明,血小板以激动剂特异性机制包装和脱落MV,
Rho GT3信号传导; Rho介导的PEV形成和包装的调节机制将被阐明。
探索目标1我们还发现PEV从血浆进入骨髓,并结合到
在体外和体内均被MK内吞。在目标2中,我们将研究血小板衍生的MV如何与
MKs具体来说,我们将确定它们与MK结合并被MK内化的机制,
他们的货物是如何转移的在SLE等炎症性疾病中,持续的血小板活化增加
循环PEV的水平。这些PEV将疾病相关变化从血浆环境直接传递给MK
在骨髓中,重新编程MK以制造更多的致病性血小板。在目标3中,我们将确定
PEV因子改变SLE中MK基因表达和血小板含量圆满完成拟议的
实验将首次提供PEV如何改变造血功能的详细路线图。
环境中的炎症性疾病。获得的见解可能会发现新的治疗靶点
(i)改变PEV的产生不依赖于血小板活化(目的1),(ii)劫持PEV/MK相互作用,以改变
MK成熟(目的2),和(iii)抑制SLE和其他炎性疾病期间的病理性MK重编程
疾病(目标3)。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kellie Rae Machlus其他文献
Kellie Rae Machlus的其他文献
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{{ truncateString('Kellie Rae Machlus', 18)}}的其他基金
The Biogenesis of Platelet-Derived Extracellular Vesicles and their Impact on Megakaryocyte Maturation
血小板源性细胞外囊泡的生物发生及其对巨核细胞成熟的影响
- 批准号:
10613503 - 财政年份:2021
- 资助金额:
$ 57.73万 - 项目类别:
The Role of CCL5 in Hematopoietic Stem Cell Activation and Skewing
CCL5 在造血干细胞激活和倾斜中的作用
- 批准号:
10348737 - 财政年份:2021
- 资助金额:
$ 57.73万 - 项目类别:
Molecular mechanisms of megakaryocyte differentiation and maturation during inflammation
炎症过程中巨核细胞分化和成熟的分子机制
- 批准号:
10290639 - 财政年份:2016
- 资助金额:
$ 57.73万 - 项目类别:
Molecular mechanisms of megakaryocyte differentiation and maturation during inflammation
炎症过程中巨核细胞分化和成熟的分子机制
- 批准号:
9221704 - 财政年份:2016
- 资助金额:
$ 57.73万 - 项目类别:
Molecular mechanisms of megakaryocyte differentiation and maturation during inflammation
炎症过程中巨核细胞分化和成熟的分子机制
- 批准号:
9352843 - 财政年份:2016
- 资助金额:
$ 57.73万 - 项目类别:
Identification of molecular pathways that initiate proplatelet formation
鉴定启动前血小板形成的分子途径
- 批准号:
8524078 - 财政年份:2014
- 资助金额:
$ 57.73万 - 项目类别:
Identification of molecular pathways that initiate proplatelet formation
鉴定启动前血小板形成的分子途径
- 批准号:
8782548 - 财政年份:2014
- 资助金额:
$ 57.73万 - 项目类别:
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