Tissue Dependent Megakaryocyte Functions

我们对血小板和巨核细胞 (Mk) 起源和功能的概念不断扩展。 Mks 位于 髓外组织，包括肺和脾。我们已经证明血小板启动、加速和 调节免疫反应的所有阶段，现在发现 Mks 具有免疫可塑性和 其功能取决于其组织环境。这包括我们发现肺部 Mks 被吸收， 过程，并将病原体衍生的抗原呈递给 T 细胞。我们的研究使我们现在假设：Mk 分化对环境病原体和/或刺激作出反应并受其支配。我们的数据还 提出了与髓外 Mk 起源和分化相关的问题。我们将利用独特的 我们合作团队的专业知识通过使用疾病相关的体外和体内小鼠模型系统来探索 这项新颖的研究调查。 本申请中提出的研究将探讨 Mks 是否与体外造血干细胞分化。 骨髓，确定 Mk 表型可塑性的环境调节因子，以及潜在的作用 免疫反应所有阶段的髓外 Mks。这些研究将确定组织驻留 Mks 在免疫反应中具有环境调节作用，改变我们对 Mk 和血小板功能的看法， 从而影响我们对发病和死亡主要原因的理解。这包括传染性 细菌性肺炎或病毒感染等疾病（例如流感和冠状病毒）。为了完成 为了实现这些范式转变目标，我们将追求以下目标： 目标#1。证明组织依赖性 Mk 分化的机制。 目标#2。证明巨核细胞的免疫调节作用。

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.