R01AI169530

ALLERGEN-INDUCED EXTRACELLULAR DNA IN TYPE 2 IMMUNITY - PROJECT SUMMARY/ABSTRACT

THE LONG-TERM OBJECTIVE OF THIS PROJECT IS TO INVESTIGATE THE FUNDAMENTAL IMMUNOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF ASTHMA AND ALLERGIC AIRWAY DISEASES.

VARIOUS ATMOSPHERIC FACTORS CONTRIBUTE TO THE PATHOGENESIS OF THESE DISEASES, INCLUDING VIRAL INFECTION, ALLERGEN EXPOSURE, AND AIR POLLUTION.

IT IS BECOMING INCREASINGLY CLEAR THAT THE AIRWAY EPITHELIUM PLAYS A KEY ROLE IN ORCHESTRATING IMMUNE RESPONSES IN THE AIRWAYS.

NONETHELESS, THE MECHANISMS INVOLVED IN THE INITIATION AND DEVELOPMENT OF IMMUNE RESPONSES TO ENVIRONMENTAL FACTORS ARE NOT FULLY UNDERSTOOD.

SENSING OF SELF-DNA BY IMMUNE CELLS HAS BEEN IMPLICATED IN STERILE INFLAMMATION IN VARIOUS ORGANS AND THE PATHOPHYSIOLOGY OF DISEASES.

WE RECENTLY FOUND THAT HUMAN AIRWAY EPITHELIAL CELLS RAPIDLY RELEASE FRAGMENTS OF NUCLEAR DNA INTO THE EXTRACELLULAR MILIEU FOLLOWING ALLERGEN EXPOSURE IN VITRO.

CASPASE-3 WAS RAPIDLY ACTIVATED IN AIRWAY EPITHELIAL CELLS UPON ALLERGEN EXPOSURE WITHOUT APPARENT SIGNS OF CELLULAR APOPTOSIS OR NECROSIS.

SELF-DNA WAS ALSO RELEASED INTO THE AIRWAY LUMEN IN NAÏVE MICE EXPOSED TO ALLERGENS IN VIVO, AND BLOCKING EXTRACELLULAR DNA (EDNA) SUPPRESSED TYPE 2 IMMUNE RESPONSES TO THE ALLERGENS.

THEREFORE, WE HYPOTHESIZE THAT ALLERGEN-INDUCED RAPID EXTRACELLULAR RELEASE OF SELF-DNA BY AIRWAY EPITHELIAL CELLS PROMOTES TYPE 2 IMMUNE RESPONSES TO AIRBORNE ALLERGENS.

THE EXPERIMENTS DESCRIBED IN THIS PROPOSAL WILL INVESTIGATE THIS HYPOTHESIS BY FOCUSING ON TWO FUNDAMENTAL QUESTIONS.

IN AIM 1, WE WILL DETERMINE HOW DNA IS RAPIDLY RELEASED BY AIRWAY EPITHELIAL CELLS IN RESPONSE TO ALLERGEN EXPOSURE IN VITRO.

WE WILL EXAMINE THE MECHANISMS OF NON-CANONICAL ACTIVATION OF CASPASE-3 AND CALPAINS, WHICH INITIATE AND TERMINATE ACTIVE DNA RELEASE, RESPECTIVELY.

IN AIM 2, WE WILL DETERMINE HOW EPITHELIUM-DERIVED EDNA PROMOTES TYPE 2 IMMUNITY AND ALLERGIC AIRWAY INFLAMMATION IN VIVO.

WE WILL INVESTIGATE THE ROLE OF THE PATTERN RECOGNITION RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS (RAGE) IN SENSING EDNA AND LEADING EXAGGERATED EFFECTOR FUNCTIONS OF GROUP 2 INNATE LYMPHOID CELLS AND CD4+ T CELLS.

WE WILL EMPLOY A COMBINATION OF COMPLEMENTARY EXPERTISE IN CELLULAR AND MOLECULAR BIOLOGY OF AIRWAY EPITHELIAL CELLS AND IMMUNOLOGY AND DISEASE MODELS OF TYPE 2 IMMUNITY IN THE LABORATORIES OF DR. O’GRADY AND DR. KITA, RESPECTIVELY.

NOVEL AND ROBUST IN VITRO AND IN VIVO MODELS HAVE BEEN DEVELOPED FOR THIS PROJECT.

THESE STUDIES WILL PROVIDE A BETTER UNDERSTANDING OF HOW AIRWAY EPITHELIUM RESPONDS TO ENVIRONMENTAL ALLERGENS AND WILL DEFINE THE KEY MOLECULES RESPONSIBLE FOR TYPE 2 IMMUNE RESPONSES IN THE AIRWAYS.

ULTIMATELY, THESE STUDIES WILL CHARACTERIZE THE CRITICAL MECHANISM(S) INVOLVED IN ALLERGEN-INDUCED IMMUNE RESPONSES, ALLOWING FOR THE IDENTIFICATION OF NOVEL THERAPEUTIC TARGET(S) FOR TREATING AND IDEALLY PREVENTING IMMUNE-MEDIATED AIRWAY DISEASES, SUCH AS ASTHMA, CHRONIC RHINOSINUSITIS, AND OTHER ALLERGIC DISORDERS.

Mayo Clinic Arizona

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]

Scottsdale, Arizona 852595404 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 387% from $649,135 to $3,163,994.