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。保持完整的肠壁屏障对于防止粘膜的微生物激活至关重要免疫。 GD上皮内淋巴细胞（IEL）在上皮室内广泛迁移到作为针对腔抗原的第一道防线和侵入性促进微生物，并且已经隐含在调节锅中抗菌胡椒的细胞分泌方面。虽然微生物衍生分子有助于GD IEL体内稳态，特定的共生细菌尚未关联随着GD IEL编号和/或功能的更改。此外，GD IEL介导的程度信号传导影响Paneth细胞功能尚未探索。在为此生成的初步数据中应用，我们确定了与与在稳态条件下扩展GD IEL。我们还表明，从WT分离出的上皮细胞 GD IEL室扩大的小鼠也暴露了涉及的基因的显着上调 Paneth细胞抗菌肽的产生和分泌。因此，该建议旨在确定各个欧元对GD IEL隔室扩展的贡献并确定 WT小鼠中GD IEL-PANETH细胞串扰的程度表现出这种超增殖表型。使用将独特鼠标模型和尖端成像结合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扩散和监视行为的扩增中阐明GD IEL是否直接促进Paneth细胞功能。对更好的理解菌群GD IEL-PANETH细胞轴可能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。