权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Immunomodulation by splenic megakaryocytes and platelets in sepsis

脓毒症中脾巨核细胞和血小板的免疫调节

基本信息

批准号：
10640199
负责人：
MARK ROBERTS LOONEY
金额：
$ 64.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-07 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640199
关键词：
Acute Adrenergic Agents Age Antibiotics Biogenesis Blood Platelets Bone Marrow Cell Therapy Cells Cessation of life Circulation Complex Data Development Engraftment Extramedullary Functional disorder Hematopoietic stem cells Heterogeneity Homeostasis Host Defense Human IL3 Gene Immune Immune response Immunity Immunologic Surveillance Immunologics Incidence Infection Inflammation Knowledge Life Lung Measures Mechanical Stress Mediator Megakaryocytes Megakaryocytopoieses Methods Morbidity - disease rate Mus Nature Organ Organ Transplantation Organ failure Peritonitis Phenotype Population Process Production Role Sampling Sepsis Site Solid Spleen Stromal Cell-Derived Factor 1 Stromal Cells Supportive care Surface Techniques Testing Therapeutic Thrombocytopenia Thrombopoiesis Transfusion Transplantation Validation acute infection adrenergic stress cytopenia design differential expression effective therapy immune function immunopathology immunoregulation individual response intravital imaging intravital microscopy mouse model novel novel therapeutic intervention pathogen pharmacologic polymicrobial sepsis progenitor response septic single-cell RNA sequencing spleen transplantation targeted treatment therapeutic evaluation

项目摘要

Project Summary Sepsis is a dysregulated host response to infection that culminates in organ failure leading to millions of deaths worldwide each year with an increasing incidence as the population ages. There is a fundamental lack of understanding of the complex host immune response in sepsis that has limited the development of targeted therapeutics for which there are none beyond antibiotics and supportive care measures. At its core, there is substantial immunopathology in sepsis with contributions from an overly exuberant immune response and ineffective pathogen clearance. We and others have studied the critical role of platelets in immune responses during acute infections, including the role of the lung in extramedullary platelet biogenesis. In this application, we will explore the role of the spleen, a central immune organ, in extramedullary megakaryopoiesis and platelet production in sepsis. Based on preliminary data, we hypothesize that the spleen co-opts a significant role in platelet biogenesis during sepsis and that the platelets produced from the spleen are immunomodulatory and important in host defense. In Aim 1, we will utilize a mouse model of peritonitis and polymicrobial sepsis resulting in thrombocytopenia to understand the mechanics of ‘stressed’ platelet biogenesis in this setting. We will study the role of adrenergic-dependent hematopoietic progenitor mobilization from the bone marrow during sepsis and the niche-promoting factors that regulate this process. In Aim 2, we will interrogate the engraftment of circulating hematopoietic progenitors in the spleen, their maturation into megakaryocytes, and the mediators (SCF, CXCL12, IL-3) regulating this process. Using state-of-the-art techniques such as intravital imaging and lineage tracing enabled by splenic transplantation, we will test the hypothesis that the spleen significantly contributes to platelet biogenesis during sepsis. In Aim 3, we will use novel methods of single-cell RNA sequencing of platelets to test for platelet heterogeneity during homeostasis and sepsis in mice and humans. Within this aim, we will test a novel cellular therapy for sepsis by transfusing immune-skewed platelets into septic mice and testing for therapeutic benefit. In summary, these studies will produce paradigm-shifting knowledge on the role of the spleen in extramedullary megakaryopoiesis and platelet production and the importance of platelet driven immunity, which will be foundational in the design of new therapeutic approaches to treat sepsis.

项目总结