R01AI165919

Immunomodulation by splenic megakaryocytes and platelets in sepsis - 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.

San Francisco Regents Of The University Of California

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

San Francisco, California 94143 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 407% from $621,176 to $3,151,437.