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Cell-cell interactions driving gut inflammation and tolerance

细胞间相互作用驱动肠道炎症和耐受性

基本信息

批准号：
10739963
负责人：
Maria Cecilia Campos Canesso
金额：
$ 13.97万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739963
关键词：
Address Advisory Committees Allergic Anti-Inflammatory Agents Antigen-Presenting Cells Antigens Automobile Driving Award CD4 Positive T Lymphocytes Cell Communication Cells Charge Colitis Color Communication Complement Dendritic Cells Development Development Plans Dietary Proteins Digestive System Disorders Disease Equilibrium Etiology Face Flow Cytometry Food Food Hypersensitivity Foundations Functional Imaging Gene Targeting Generations Genes Genetic Goals Health Homeostasis Hypersensitivity Image Immune Immune response Immune system Immunity Immunology Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Intestinal Diseases Intestines Label Location Mentors Mentorship Microbe Molecular Mucosal Immune Responses Mucous Membrane Mus Nature Nutrient Outcome Pathologic Pathway interactions Phase Physiological Population Predisposition Process Property Public Health Reaction Regulatory T-Lymphocyte Research Research Personnel Research Proposals Resources Role Stimulus System T cell differentiation T-Cell Activation T-Lymphocyte Technology Testing Training Universities Work career development commensal bacteria confocal imaging dietary draining lymph node effector T cell enteric infection enteric pathogen functional outcomes gut inflammation gut microbiota host-microbe interactions ileum imaging genetics in vivo insight intestinal barrier intestinal homeostasis microbiome microbiota microorganism antigen migration mouse genetics new technology new therapeutic target novel novel therapeutics oral tolerance pathogen preservation prevent programs rational design response single-cell RNA sequencing tool transcriptomics

项目摘要

Project summary The highly specialized intestinal immune system is charged with maintaining tolerance to harmless stimuli from food and commensal bacteria, while providing protective immunity against pathogens. Dysregulation of this critical balance can lead to food allergy, inflammatory bowel disease (IBD), or increased susceptibility to enteric pathogens. Dendritic cells (DCs) are key players in intestinal homeostasis, finely orchestrating immune responses by presenting luminal antigens and inducing functional differentiation of CD4+ T cells into regulatory or pro-inflammatory subsets. The cellular mechanisms underlying the decision between tolerance or immunity to intestinal antigens remain unknown, largely because the identification and characterization of the exact DCs involved in these processes has been a decades-long technical challenge. To overcome this problem, I established the use of the LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts) technology in the gut, which enables proximity-dependent labeling of specific intestinal cell-cell interactions. The main goal of this research proposal is to elucidate the mechanisms that determine whether DCs will induce regulatory or pro-inflammatory T cells in vivo, by combining the LIPSTIC system with gene targeting, functional imaging, intersectional genetics, and interaction-based transcriptomics approaches. This proposal tests the hypothesis that DCs specialized for different functions exist in the intestine and that continuous dynamic reprogramming of DCs subsets by luminal content dictate tolerance or immunity to food and microbes. Specifically, this concept will be tested in mice under physiological (tolerance to food and microbes) and pathological (allergic sensitization, enteric infection, and colitis) scenarios. To this end, the K99 mentored phase (Aim 1) will reveal the exact nature of the DCs that induce tolerance or inflammation to food and the cellular and molecular mechanisms by which food-specific pTregs maintain oral tolerance. Next, the R00 independent phase (Aim 2) will focus on studying immune responses to commensals, with relevance to disorders such as colitis. Elucidating the DC populations, location and molecular mechanisms involved in tolerance to distinct microbes will reveal the nature of host-microbe interactions in health and disease. Together, this research program will lend fundamental insight into the etiology of certain intestinal disorders and will provide foundation for the development of new therapies for food allergy, colitis, and enteric infections, with profound implications for public health. The proposed development plan complements my training in mucosal immunology and cellular interactions with transcriptomics analysis, imaging, and mouse genetics. I will take advantage of the extensive resources of the Rockefeller University, the mentorship of Dr. Daniel Mucida, Dr. Gabriel Victora and the Advisory Committee team that will lend expertise in key aspects of the project and career development. At the end of the mentored phase, I will be equipped with the necessary tools to conduct comprehensive studies at the intersection of cellular communication and immune response to commensals as an independent investigator.

项目总结