Megakaryocyte Mechanosensing Toward Platelet Biogenesis

巨核细胞机械传感对血小板生物发生的影响

基本信息

批准号：
10473789
负责人：
KATYA RAVID
金额：
$ 41.25万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
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：
2021-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10473789
关键词：
Actins Address Adhesions Adult Affect Area Basement membrane Biogenesis Biology Blood Platelets Blood Vessels Bone Marrow Calcium Cations Cell physiology Cells Collagen Collagen Receptors Collagen Type IV Cytoskeleton Development Environment Extracellular Matrix Extracellular Matrix Proteins Family Fibronectin Receptors Fibronectins Generations Genetic Goals Greek Hemorrhage Hemostatic function Human Image In Vitro Integrins Intravenous Immunoglobulins Investigation Knock-out Knockout Mice Knowledge Life Marrow Measurement Mechanics Mechanoreceptors Mediating Megakaryocytes Mus Myelosuppression Neurons Outcome Pathology Pathway interactions Patients Pharmacology Phenotype Piezo 1 ion channel Piezo 2 ion channel Platelet Count measurement Platelet Transfusion Play Ploidies Production Property Proteins Receptor Activation Reporting Research Research Proposals Role Signal Transduction Testing Thrombocytopenia Thrombopoietin Thrombosis Transfusion Tubulin attenuation blood product crosslink experimental study high risk in vivo innovation insight leukemia mechanotransduction member mimetics mouse model novel preference pressure prevent receptor response side effect thrombocytosis thrombotic transcription factor translational potential

Actins Address Adhesions Adult Affect Area Basement membrane Biogenesis Biology Blood Platelets Blood Vessels Bone Marrow Calcium Cations Cell physiology Cells Collagen Collagen Receptors Collagen Type IV Cytoskeleton Development Environment Extracellular Matrix Extracellular Matrix Proteins Family Fibronectin Receptors Fibronectins Generations Genetic Goals Greek Hemorrhage Hemostatic function Human Image In Vitro Integrins Intravenous Immunoglobulins Investigation Knock-out Knockout Mice Knowledge Life Marrow Measurement Mechanics Mechanoreceptors Mediating Megakaryocytes Mus Myelosuppression Neurons Outcome Pathology Pathway interactions Patients Pharmacology Phenotype Piezo 1 ion channel Piezo 2 ion channel Platelet Count measurement Platelet Transfusion Play Ploidies Production Property Proteins Receptor Activation Reporting Research Research Proposals Role Signal Transduction Testing Thrombocytopenia Thrombopoietin Thrombosis Transfusion Tubulin attenuation blood product crosslink experimental study high risk in vivo innovation insight leukemia mechanotransduction member mimetics mouse model novel preference pressure prevent receptor response side effect thrombocytosis thrombotic transcription factor translational potential

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项目摘要

ABSTRACT Platelet counts are tightly regulated in order to prevent thrombotic or hemorrhagic complications associated with thrombocytosis or thrombocytopenia, respectively. While strides have been made in our understanding of proplatelet formation (PPF), there is still limited knowledge regarding the mechanisms through which the bone marrow (BM) extracellular matrix (ECM) regulates platelet production. Indeed, the BM includes a rich ECM with potential to generate mechanical constraints. Yet, the impact of BM mechanics on megakaryocyte (MK) properties and platelet formation has been understudied. Here, we propose an integrative approach to investigate emerging concepts related to the role of MK mechanobiological receptors in controlling MK adhesion to the ECM and platelet production. Our ultimate goal is to understand how specific MK mechanosensors sense the BM matrix to affect the cellular cytoskeleton, MK properties and, importantly, platelet level. Building upon our novel findings, Aim 1 explores the new paradigm and hypothesis that distinct MK cation channels preferentially respond to different BM matrix proteins and inversely impact the MK cytoskeleton and platelet levels. Experiments will focus on the Piezo family of cation channel mechanosensors, as compared to the Transient Receptor Potential cation channel subfamily V member 4 mechanosensor. In recent studies, we found these mechanosensors to have distinct preferences for different matrix proteins and opposing effects on PPF. Investigations will be carried out using pharmacological approaches as well as newly generated knockout mice at baseline and in response to challenges, such as myelosuppression or thrombocytopenia. Encouraged by preliminary studies using human primary MKs, continued studies will confirm murine findings. Aim 2 delineates mechanisms mediating novel connections between MK mechanosensors, integrin receptors activation, cytoskeletal changes, and MK mechano-sensitive transcription factors. This proposal is significant as there is need to identify new and alternative thrombopoietic pathways and agents that modulate platelet counts. In addition to conceptual innovation, at the technical level we will analyze new mouse models we developed with deletion of specific mechanosensors in MKs, and will apply state-of-the-art imaging and measurements under flow to follow cellular processes. Proposed studies are expected to yield new insights on the role of selective ECM sensing by MKs in controlling the MK cytoskeleton, adhesion and platelet production, with significant potential to impact our ability to modulate platelet levels.

抽象的血小板计数受到严格调节，以防止血栓形成或出血并发症分别患有血小板病或血小板减少症。尽管我们对我们的理解取得了进步预言形成（PPF），关于骨头的机制知识仍然有限骨髓（BM）细胞外基质（ECM）调节血小板的产生。确实，BM包括一个丰富的ECM 产生机械约束的潜力。然而，BM力学对巨核细胞（MK）的影响特性和血小板的形成已被研究。在这里，我们提出了一种综合方法研究与MK机械生物学受体控制MK的作用相关的新兴概念对ECM和血小板产生的粘附。我们的最终目标是了解特定的MK 机械传感器感知BM基质会影响细胞细胞骨架，MK特性，并且重要的是血小板级别。在我们的新颖发现的基础上，AIM 1探索了新的范式和假设 MK阳离子通道优先响应不同的BM基质蛋白，并成反对MK 细胞骨架和血小板水平。实验将集中于阳离子通道机械传感器的压电家族，与瞬态受体潜在阳离子通道亚家族V成员4机械传感器相比。在最近的研究，我们发现这些机械传感器对不同基质蛋白和对PPF的反对影响。调查将使用药理学方法以及新的基线时产生的淘汰小鼠以及响应挑战，例如骨髓抑制或血小板减少症。在使用人类主要MK的初步研究的鼓励下，将继续研究确认鼠的发现。 AIM 2描述了介导MK之间新型连接的机制机械传感器，整联蛋白受体激活，细胞骨架变化和MK机械敏感性转录因素。该提议很重要，因为需要识别新的和替代性的血小板途径和调节血小板计数的药物。除了概念创新，在技术层面上，我们还将分析我们在MK中使用特定机械传感器删除开发的新鼠标模型，并将应用在流动下进行的最新成像和测量，以遵循细胞过程。拟议的研究是预计将通过MK在控制MK细胞骨架中的选择性ECM传感的作用中产生新的见解，粘附和血小板产生，具有影响我们调节血小板水平的能力的巨大潜力。