U01AI170018

Mechanisms of Radiation-Induced Innate Immune Dysfunction and Its Countermeasures - Project Description:

Nuclear power plant accidents, terrorism, and geopolitical instability present the risk of massive radiation exposure. As neutrophils markedly decline post-radiation exposure, macrophages assume the important role of removing most translocated or invading bacteria. However, very few studies have evaluated the effects of radiation on the phagocytic function of differentiated, non-dividing tissue resident macrophages.

We have discovered that extracellular cold-inducible RNA-binding protein (ECIRP) is a novel mediator which can cause innate immune dysfunction. In our preliminary studies, we have shown an increased release of ECIRP after radiation exposure in vivo and in vitro. Deficiency in CIRP improved the survival of mice subjected to total body irradiation (TBI). Sepsis significantly worsened the survival post-TBI, but CIRP-/- mice had lower bacterial loads and improved survival after sepsis, suggesting that ECIRP's detrimental effect may be due to the impaired bacterial clearance.

Indeed, ECIRP significantly reduced macrophage phagocytosis of E. coli via cytoskeletal paralysis. ECIRP also induced the formation of macrophage extracellular traps, and extracellular traps reduced macrophage phagocytosis of dying cells. We have identified that triggering receptor expressed on myeloid cells-1 (TREM-1) is the ECIRP receptor, and that TREM-1 activation plays a critical role in the ECIRP-mediated macrophage phagocytic dysfunction. Moreover, the 30-day survival after TBI was significantly improved in TREM-1-/- mice.

Based on these novel findings, we hypothesize that ECIRP released after ionizing radiation activates TREM-1, resulting in macrophage phagocytic dysfunction and ultimately leading to sepsis and death. We have also shown that the new inhibitor M3 reduced ECIRP's binding to TREM-1 and improved survival after sepsis. As such, we further hypothesize that inhibition of ECIRP/TREM-1 interaction with M3 restores macrophage phagocytic function, thereby improving the survival of mice subjected to radiation injury alone or complicated by sepsis.

In this project, we plan to further establish the critical role of ECIRP on radiation-induced macrophage phagocytic dysfunction, determine the mechanisms by which ECIRP causes macrophage phagocytic dysfunction, and develop M3 as a novel radiation medical countermeasure targeting ECIRP-induced macrophage phagocytic dysfunction. These studies shall provide novel mechanistic insights into the pathogenesis of radiation-induced innate immune dysfunction, as well as a new medical countermeasure for victims of major radiation exposure with or without sepsis.

The Feinstein Institutes For Medical Research

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.

93.310 - Trans-NIH Research Support

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

Manhasset, New York 110303816 United States

Single Zip Code

Radiation-Induced Immune Dysfunction (U01 Clinical Trial Not Allowed) (RFA-AI-21-019)

Amendment Since initial award the total obligations have increased 314% from $726,622 to $3,005,089.