Tissue Dependent Megakaryocyte Functions

我们对血小板和巨核细胞(MK)来源和功能的概念在继续扩展。MK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 依赖于其组织环境的功能。这包括我们的发现，肺MKs占据了， 处理，并将病原体来源的抗原呈递给T细胞。我们的研究使我们现在假设：MK 分化是对环境病原体和/或刺激的反应和支配。我们的数据也 提出与髓外MK起源和分化有关的问题。我们将利用独一无二的 我们合作团队的专业知识通过使用与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。 这一应用中的拟议研究将探索MKs是否从体外的造血干细胞分化而来 骨髓，确定Mk表型可塑性的环境调节因素，以及在 髓外MKs存在于免疫反应的各个阶段。这些研究将确定组织驻留的MKS 在免疫反应中发挥环境调节作用，改变我们看待巨噬细胞和血小板功能的方式， 从而影响我们对发病率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(例如流感和冠状病毒)。要完成 在这些范式转变目标中，我们将追求以下目标： 目的：1.探讨组织依赖性巨噬细胞分化的机制。 目的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.