Tissue Dependent Megakaryocyte Functions

组织依赖性巨核细胞功能

• 批准号: 10569096
• 负责人: CRAIG N MORRELL
• 金额: $ 50.91万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-08 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569096
• 关键词: Acceleration; Acute-Phase Reaction; Affect; Antigen Presentation; Antigens; Bacterial Pneumonia; Biological Models; Blood Platelets; Bone Marrow; CD8-Positive T-Lymphocytes; Cell Differentiation process; Cells; Communicable Diseases; Coronavirus; Data; Development; Disease; Disease Outcome; Environment; Extramedullary; Goals; Helper-Inducer T-Lymphocyte; Hematopoietic stem cells; Homeostasis; Immune; Immune response; Immune system; In Vitro; Infection; Inflammatory; Influenza; Interdisciplinary Study; Journals; Lung; Maintenance; Mediating; Mediator; Megakaryocytes; Morbidity - disease rate; Pathogenicity; Phase; Phenotype; Platelet Count measurement; Process; Production; Publishing; Research; Research Personnel; Response to stimulus physiology; Role; Shapes; Source; Spleen; Stimulus; T-Lymphocyte; Thrombosis; Tissues; Virus Diseases; Work; clinical investigation; hematopoietic differentiation; in vivo; monocyte; mortality; mouse model; novel; pathogen; platelet function; progenitor; response; tissue injury; trafficking; uptake; working group

Our concepts of platelet and megakaryocyte (Mk) origins and functions continue to expand. Mks are found in extramedullary tissues, including the lungs and spleen. We have shown that platelets initiate, accelerate, and regulate all phases of the immune responses and have now discovered that Mks have immune plasticity and functions that are dependent on their tissue environment. This includes our discovery that lung Mks take up, process, and present pathogen derived antigens to T cells. Our studies lead us to now hypothesize that: Mk differentiation is responsive to, and dictated by, environmental pathogens and/or stimuli. Our data also presents questions related to extramedullary Mk origins and differentiation. We will leverage the unique expertise of our collaborative team by using disease relevant in vitro and in vivo mouse model systems to explore this novel research inquiry. Proposed studies in this application will explore whether Mks differentiate from hematopoietic stem cells outside the bone marrow, determine the environmental regulators of Mk phenotype plasticity, and potential roles for extramedullary Mks in all phases of the immune responses. These studies will establish that tissue resident Mks have environmentally regulated roles in immune responses, changing how we view Mk and platelet functions, thereby impacting our understanding of major causes of morbidity and mortality. This includes infectious diseases such as bacterial pneumonias or viral infections (examples; influenza and coronavirus). To accomplish these paradigm shifting goals, we will pursue the following Aims: Aim #1. To demonstrate mechanisms of tissue dependent Mk differentiation. Aim #2. To demonstrate megakaryocyte immune regulatory roles.

我们对血小板和巨核细胞（MK）起源和功能的概念不断扩展。 MK在 外的组织，包括肺和脾脏。我们已经表明，血小板启动，加速和 调节免疫反应的所有阶段，现在发现MK具有免疫可塑性，并且 取决于其组织环境的功能。这包括我们发现肺MK占据的发现， 过程，并呈现病原体衍生成T细胞的抗原。我们的研究使我们现在假设：MK 分化对环境病原体和/或刺激的反应和决定。我们的数据也是如此 提出了与耗尽MK的起源和分化有关的问题。我们将利用独特的 通过使用疾病相关的体外和体内鼠标模型系统来探索我们协作团队的专业知识 这个新颖的研究调查。 该应用中提出的研究将探索MK是否与造血干细胞区分开 骨髓，确定MK表型可塑性的环境调节剂，以及潜在的作用 免疫反应的所有阶段中的耗尽MK。这些研究将确定组织常驻MK 在免疫反应中具有环境调节的作用，改变了我们对MK和血小板功能的看法， 从而影响我们对主要原因和死亡率的主要原因的理解。这包括传染性 细菌性肺炎或病毒感染等疾病（例子；流感和冠状病毒）。完成 这些范式转移的目标，我们将追求以下目标： 目标＃1。证明组织依赖的MK分化机制。 目标＃2。展示巨核细胞免疫调节作用。