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Principal Investigator: Gregory F Sonnenberg
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $508,500
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT ABSTRACT
The gastrointestinal tract is colonized with trillions of normally beneficial microbes, termed the microbiota, that
are essential for human health. However, the pathogenesis of numerous infectious, inflammatory, and
metabolic diseases involves a loss of immunologic tolerance to the gut microbiota. This has been
demonstrated robustly in basic, translational, and clinical studies of inflammatory bowel disease (IBD). The
fundamental focus of our proposed renewal for R01AI123368 is to build on recent paradigm-shifting
results from the first funding cycle that detailed a novel pathway that is essential to orchestrate
immune tolerance to gut microbiota and restrain intestinal inflammation. Specifically, our prior studies
detailed how group 3 innate lymphoid cells (ILC3s) present microbiota-derived antigens to CD4 T cells on
MHCII, instruct the differentiation of a unique form of RORgt+ regulatory T cells (Tregs), and prevent
spontaneous intestinal inflammation. Further, we find that these cellular interactions are dysregulated in the
inflamed intestine of individuals with IBD (see Zhou et al., Nature, 2022 and Lyu et al., Nature, 2022 as the
most recent examples). We generated new preliminary data to support this renewal application where we
propose to mechanistically advance this paradigm and will explore the therapeutic potential of our key findings.
This includes three specific aims, which will: (i) define how ILC3s sense microbiota to initiative antigen
presentation, (ii) elucidate key molecular determinants endowing a tolerogenic program in MHCII+ ILC3s, and
(iii) identify whether MHCII+ ILC3s can be harnessed to enforce tolerance to diverse microbes or restrain gut
inflammation as a pre-clinical therapy. We will employ basic mouse models, as well as translate our findings
into human specimens. This research is directly relevant to IBD and many other chronic inflammatory diseases
where disruptions to immune tolerance underlie disease pathogenesis, and it is expected that our mechanistic
results will provoke new opportunities for preventative, therapeutic or curative treatment strategies.
Terms: <Address><Alimentary Canal><American><Antigen Presentation><Antigen-Presenting Cells><Antigens><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CUT&RUN><Cell Communication and Signaling><Cell Signaling><Chronic><Class II Antigens><Class II Major Histocompatibility Antigens><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Clinical Research><Clinical Study><Communicable Diseases><DNA><Data><Deoxyribonucleic Acid><Digestive Tract><Disease><Disorder><Endowment><Funding><GI Tract><GI microbiota><Gastrointestinal Tract><Gastrointestinal microbiota><Gastrointestinal tract structure><Gene Transcription><Gene variant><Genes><Genetic><Genetic Transcription><Health><Histocompatibility Antigens Class II><Homing><Human><I-A Antigen><IFN><Ia Antigens><Ia-Like Antigens><Immune><Immune Response Antigens><Immune Tolerance><Immune system><Immune-Response-Associated Antigens><Immunes><Immunologic Tolerance><Immunomodulation><Individual><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Interferons><Intestinal><Intestines><Intracellular Communication and Signaling><Investigation><Knowledge><Link><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Lymphoid Cell><MHC Class II Molecule><MHC Class II Protein><MHC Receptor><MHC class II antigen><Major Histocompatibility Complex Class II><Major Histocompatibility Complex Receptor><Mediating><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Microbe><Modern Man><Molecular><Murine><Mus><Nature><Pathogenesis><Pathway interactions><Process><Property><Publishing><RNA Expression><Regulation><Regulatory T-Lymphocyte><Research><Research Specimen><Role><Seminal><Signal Transduction><Signal Transduction Systems><Signaling><Specimen><Symbiosis><T cell differentiation><T cell response><T-Cell Activation><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Testing><Therapeutic><Thesaurismosis><Transcription><Transcription Repressor><Transcriptional Repressor><Translating><Treg><accessory cell><activate T cells><alimentary tract><allele variant><allelic variant><beneficial flora><beneficial microbes><beneficial microflora><beneficial microorganism><biological signal transduction><bowel><bowel inflammation><cell type><chronic inflammatory disease><commensalism><curative intervention><curative therapeutic><curative therapy><curative treatments><cytokine><digestive canal><draining lymph node><enteric microbial community><enteric microbiota><gastrointestinal microbial flora><genetic repressor><genetic variant><genomic variant><germ free condition><gut commensal><gut community><gut flora><gut health><gut inflammation><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><health economics><host microbiota><host microflora><immune modulation><immune regulation><immune system tolerance><immune unresponsiveness><immunogen><immunologic reactivity control><immunological paralysis><immunomodulatory><immunoregulation><immunoregulatory><imprint><inflamed bowel><inflamed gut><inflamed intestine><inflammatory disease of the intestine><inflammatory disorder of the intestine><intestinal autoinflammation><intestinal flora><intestinal inflammation><intestinal microbiota><intestinal microflora><intestinal tract microflora><lymph gland><lymph nodes><lymphnodes><metabolism disorder><microbial><microbial consortia><microbial flora><microbiota><microflora><migration><mouse model><multispecies consortia><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><pre-clinical><pre-clinical therapy><preclinical><preclinical therapy><preservation><prevent><preventing><programs><regional lymph node><regulatory T-cells><resident microbes><resident microflora><restraint><sensor><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><specific pathogen free><therapeutic evaluation><therapeutic testing><thymus derived lymphocyte><translational study><treatment strategy>