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）的起源和功能的概念不断扩大。在