R01AI188710

Study the TREG-IL-27 axis in immune regulation.

Regulatory T (TREG) cells, a specialized immune population, are known for their role in maintaining immunological tolerance.

Mounting evidence has suggested that TREG cells not only come in “different flavors” phenotypically and functionally and play distinct roles in different tissue microenvironments.

Consistent with these findings, our previous analysis of tissue TREG cell transcriptome profiling data has revealed unexpectedly elevated expression of IL-27, specifically in gut-associated TREG cells isolated from inflammatory settings.

In humans, genome-wide association studies have identified IL-27 as a candidate gene within a susceptibility locus for inflammatory bowel disorder (IBD).

Significantly, less IL-27 was found in people harboring the risk alleles relative to those with the nonrisk alleles.

These studies provided evidence linking IL-27 and IBD and suggested that the observed elevations in IL-27 in certain patients probably represent an anti-inflammatory response, albeit insufficient to control the ongoing intestinal inflammation.

In this application, by using TREG cell-specific gene targeting approaches, our preliminary results have shown that TREG cell-derived IL-27 is crucial to control TH17 immunity particularly in the intestinal tissue.

Further single-cell RNA sequencing (scRNA-seq) analysis has identified a CD83+CD62LLO TREG cell subset that is distinct from previously characterized intestinal TREG cell populations as the main IL-27 producers.

Nevertheless, the molecular mechanisms and the environmental factors that drive the expression of IL-27 specifically in gut TREG cells during inflammation remain poorly defined.

Through employing molecular, biochemical, and immunological approaches with whole animal experimentation, we will first examine the TREG cell-intrinsic molecular mechanisms accounted for the induction of IL-27 in intestinal TREG cells particularly under inflammatory conditions.

Next, as the intestine is a special tissue location colonized by over 100 trillion commensal microorganisms that have been shown to be crucial in modulating TREG cell biology and T cell immunity, by employing cutting-edge microbiome technologies, as well as mice with microbiome interventions, we will identify and functionally validate the potential microbes that contribute to the induction of IL-27 in gut TREG cells.

Accomplishing the aims proposed in this application will undoubtedly extend our fundamental knowledge of the TREG cell-IL-27 axis in maintaining intestinal homeostasis and provide further insights into tissue-specific TREG cell-mediated immune regulation under different cellular and environmental settings.

San Diego 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]

La Jolla, California 92093 United States

Single Zip Code

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