Tissue Dependent Megakaryocyte Functions

我们的概念血小板和巨核细胞（Mk）的起源和功能继续扩大。MKS被发现在 髓外组织，包括肺和脾。我们已经证明，血小板启动，加速， 调节免疫反应的所有阶段，现在已经发现Mks具有免疫可塑性， 这些功能依赖于它们的组织环境。这包括我们发现肺Mks摄取， 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 分化响应于环境病原体和/或刺激并受其支配。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 通过使用疾病相关的体外和体内小鼠模型系统， 这个新奇的研究调查 本申请中的拟议研究将探索Mks是否从外部造血干细胞分化 骨髓，确定Mk表型可塑性的环境调节因子，以及 髓外Mks在免疫反应的所有阶段。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，改变了我们对Mk和血小板功能的看法， 从而影响我们对发病率和死亡率主要原因的理解。其中包括传染性 细菌性肺炎或病毒感染等疾病（例如：流感和冠状病毒）。完成 这些范式转变的目标，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。探讨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.