Microbiota-gamma delta IEL-Paneth cell axis in host antimicrobial response

宿主抗菌反应中的微生物群-γ δ IEL-潘氏细胞轴

基本信息

批准号：
10817443
负责人：
Karen Leigh Edelblum
金额：
$ 21.05万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10817443
关键词：
Affect American Anti-Bacterial Agents Antigens Behavior Bilophila Biological Process Cell Degranulation Cell Separation Cell physiology Cell secretion Cells Chronic Coculture Techniques Communicable Diseases Communication Crohn&apos s disease Data Development Disease Disease remission Enteral Enterocytes Epithelial Cells Epithelium Exhibits Extracellular Space Family First Degree Relative Frequencies Gene Expression Regulation Genes Germ-Free Goals Homeostasis Host Defense Human Ileal Diseases Ileitis Imaging technology Immune Immune System Diseases Immune system Immunologic Surveillance In Vitro Individual Inflammatory Inflammatory Bowel Diseases Intestines Knowledge Lateral Lymphocyte Maintenance Mediating Microbe Mission Modeling Mucosal Immune System Mucosal Immunity Mucous Membrane Mus National Institute of Allergy and Infectious Disease Paneth Cells Pathology Patients Permeability Phenotype Population Production Proliferating Public Health Receptor Cell Reporter Research Role Signal Transduction Small Intestines Speed T-Cell Receptor T-Lymphocyte Therapeutic United States National Institutes of Health Up-Regulation Variant Villous Work antimicrobial antimicrobial peptide cell type commensal bacteria enteric infection experimental study gut inflammation human disease immunoregulation in vivo insight intestinal barrier intestinal epithelium intestinal homeostasis intraepithelial microbial microbiota migration mouse model new therapeutic target novel novel therapeutic intervention prevent receptor-mediated signaling response transcriptome sequencing

项目摘要

PROJECT SUMMARY. Maintenance of an intact intestinal barrier is critical to prevent microbial activation of mucosal immunity. gd intraepithelial lymphocytes (IEL) migrate extensively within the epithelial compartment to serve as a first line of defense against luminal antigens and invasive enteric microbes, and have been implicating in regulating Paneth cell secretion of antimicrobial peptides. Although microbial-derived molecules contribute to gd IEL homeostasis, specific commensal bacteria have yet to be associated with alterations in gd IEL number and/or function. Moreover, the extent to which gd IEL-mediated signaling influences Paneth cell function has yet to be explored. In preliminary data generated for this application, we identified 5 amplicon sequence variants (ASV) that are strongly associated with the expansion of gd IELs under homeostatic conditions. We also show that epithelial cells isolated from WT mice with an expanded gd IEL compartment also exhibit a significant upregulation of genes involved in Paneth cell antimicrobial peptide production and secretion. Therefore, this proposal seeks to identify the contribution of individual commensals to the expansion of the gd IEL compartment and determine the extent of gd IEL-Paneth cell crosstalk in WT mice exhibiting this hyperproliferative phenotype. Using an integrated approach that combines unique mouse models and cutting edge imaging technologies both in vitro and in vivo, these studies will be the first to identify the contribution of individual commensals in the amplification of gd IEL proliferation and surveillance behavior, and elucidate whether gd IELs directly promote Paneth cell function. Developing a better understanding of the microbiota-gd IEL-Paneth cell axis may identify novel therapeutic targets to aid in host defense and help maintain remission in Crohn’s disease patients.

项目摘要。维持完整屏障对于预处理微生物的粘膜激活至关重要免疫力。作为针对腔抗原和侵入性肠道微生物的AST防御线，已经与调节抗菌肽的泛细胞分泌有关。分子有助于GD IEL稳态，特定的共生细菌尚未关联随着GD IEL数量/功能的更改，GD IEL介导的程度信号影响Paneth Cell功能尚未在生成的初步数据中探索应用，我们确定了与与在稳态条件下的GD IEL的扩展。具有Anded GD IEL室的小鼠也表现出对参与基因的显着上调 Paneth细胞抗菌肽肽肽和分泌。个体评论对GD IEL车厢扩展的贡献并确定 WT小鼠中GD IEL-PANETH细胞串扰的程度表现出这种超增殖表型。使用结合独特鼠标模型和尖端成像的集成方法在体外和体内技术，这些研究将是第一个确定的贡献在GD IEL的繁殖和监视行为的扩增中，各个欧元阐明GD IEL是否直接促进Paneth细胞功能。微生物群IEL-PANETH细胞轴可能会识别出新的治疗靶标，以帮助宿主防御和有助于维持克罗恩病患者的缓解。