R01AI184441

DENDRITIC CELL INTRINSIC UPR IS CRITICAL FOR PATHOGEN SPECIFIC TH17 RESPONSES - PROJECT SUMMARY FOLLOWING AC+VA+ON, CD4 T CELLS DIFFEREN+ATE INTO ONE OF THREE MAIN EFFECTOR LINAGES. THE TH1, TH2 AND TH17 LINEAGE CELLS ARE GENERATED IN RESPONSE TO SPECIFIC CLASS OF PATHOGENS AND ARE NECESSARY TO COMBAT THOSE INFEC+ONS. WHILE WE HAVE COMPREHENSIVE UNDERSTANDING OF THE SPECIFIC CYTOKINE CUES AS WELL AS MASTER TRANSCRIP+ON FACTORS THAT ARE CRI+CAL FOR DIFFEREN+A+ON OF EACH OF THESE DIS+NCT T CELL EFFECTOR LINEAGES, THE INNATE SENSING MECHANISMS THAT DICTATE SPECIFIC DIFFEREN+A+ON OF EACH OF THE T EFFECTOR LINEAGES ARE NOT CLEAR. THE PATHOGENS THAT DRIVE TH2 RESPONSES ARE FAIRLY DIS+NCT BUT THE TH1 AND TH17 INDUCING PATHOGENS SHARE MANY STRUCTURAL SIMILARI+ES. CLASSICAL PAFERN RECOGNI+ON RECEPTOR AC+VA+ON BY MICROBIAL LIGANDS LEADS TO GENERA+ON OF INFLAMMATORY CYTOKINE CUES IN THE FORM OF TNF, IL-6, IL-12, IL-1B, ETC BUT WE DO NOT UNDERSTAND HOW CD4 T CELLS INTEGRATE SPECIFIC CUES TO GENERATE A TH1 VS TH17 RESPONSE. WE POSIT HERE THAT HOST SENSING MECHANISMS THAT EXTEND BEYOND THE CLASSICAL PAFERN RECOGNI+ON RECEPTORS MIGHT BE INVOLVED IN GENERA+NG UNIQUE CYTOKINE CUES THAT SPECIFICALLY DICTATE GENERA+ON OF TH1 VS TH17 LINEAGE CELLS. OUR PREVIOUS WORK HAS DEMONSTRATED THAT FOLLOWING SENSING OF PATHOGENS, CONVEN+ONAL DCS CAN INDUCE PRIMING OF NAÏVE PATHOGEN SPECIFIC CD4 T CELLS IN VITRO AND THE QUALITY OF THE T CELL RESPONSE IS DICTATED BY THE NATURE OF THE PRIMING PATHOGEN. SPECIFICALLY, S+MULA+ON OF CONVEN+ONAL DCS WITH THE GUT PATHOGEN C. RODEN)UM DRIVES TH17 DIFFEREN+A+ON AS OPPOSED TO L. MONOCYTOGENES, SUGGES+NG A DC-DEPENDENT MECHANISM FOR TH17 DIFFEREN+A+ON. TRANSCRIP+ONAL PROFILING OF DCS UPON EXPOSURE TO TH17 INDUCING (C. RODEN)UM) VERSUS NON-INDUCING PATHOGENS (L. MONOCYTOGENES AND S. AUREUS) AND DISCOVERED THAT C. RODEN+UM INDUCED AC+VA+ON OF THE PERK PATHWAY OF UNFOLDED PROTEIN RESPONSE (DC- UPR) THAT WAS INTEGRAL TO ITS ABILITY TO INDUCE TH17 RESPONSES. C. RODEN+UM’S ABILITY TO INDUCE DC-UPR WAS SHARED BY ITS COUNTERPARTS, THE HUMAN ENTERIC PATHOGENS, EHEC AND EPEC SUGGES+NG THAT THIS PROPERTY WAS EVOLU+ONARILY CONSERVED IN BOTH THE MICROBES AND THE HOSTS. MORE IMPORTANTLY, SEVERAL AUTOIMMUNE DISEASES CAUSED BY TH17 CELLS ARE ASSOCIATED WITH THE UNFOLDED PROTEIN RESPONSE SUGGES+NG AN INTEGRAL LINK BETWEEN ER STRESS AND OUTCOME OF T CELL RESPONSES. IN THIS APPLICA+ON WE PROPOSE TO INVES+GATE THE IMPORTANCE OF THIS UPR INDUC+ON FROM THE PERSPEC+VE OF THE MICROBE AS WELL AS THE HOST AND DISSECT THE MOLECULAR MECHANISMS OF INDUC+ON OF THE UPR AND ITS IMPACT ON TH17 PRIMING AND DIFFEREN+A+ON. IN AIM 1, WE WILL INVES+GATE THE ROLE OF DC-UPR IN DRIVING TAILORED IMMUNE RESPONSES AGAINST TH17 INDUCING PATHOGENS. IN AIM, 2 WE WILL IDEN+FY AND CHARACTERIZE THE NATURE OF THE C. RODEN+UM LIGAND THAT AC+VATES THE PERK PATHWAY OF UPR IN DCS. IN AIM 3, WE WILL INVES+GATE THE CONSERVED NATURE OF THE UPR PATHWAY IN HUMAN ENTERIC PATHOGENS AND HUMAN MYELOID CELLS. SUCCESSFUL COMPLE+ON OF THESE AIMS WILL ADD TO OUR FUNDAMENTAL UNDERSTANDING OF GENERA+ON OF TH17 RESPONSES AND WILL PROVIDE US WITH TOOLS TO EITHER INCREASE OR MI+GATE DEVELOPMENT OF TH17 RESPONSE TO ENHANCE PROTEC+ON AGAINST PATHOGENS OR PROTECT AGAINST AUTO-IMMUNE INFLAMMA+ON.

Childrens Hospital Medical Center

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]

Cincinnati, Ohio 45229 United States

Single Zip Code

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