Regulation of Gut Innate Lymphoid Cells by Ahr

Ahr 对肠道先天淋巴细胞的调节

基本信息

批准号：
10187510
负责人：
Liang Zhou
金额：
$ 52.48万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2023-05-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10187510
关键词：
Allergic Disease Aryl Hydrocarbon Receptor Autoimmunity Cell Differentiation process Cell physiology Cells Cellular biology Chromatin Data Development Diet Dietary Component Disease Dose Environment Environmental Impact Environmental Risk Factor Epithelial Cells Equilibrium Exhibits Family Fatty acid glycerol esters GATA3 gene Gene Expression Profile Genetic Genetic Transcription Germ-Free Human Immune Immunity Infection Inflammation Inflammatory Bowel Diseases Injury Interleukin-13 Interleukin-5 Intestines Ligands Lung Lymphoid Cell Maintenance Mediating Microbe Modeling Molecular Molecular Mechanisms of Action Mucous Membrane Mus Natural Killer Cells Pathogenesis Pathway interactions Physiological Play Prevention Production Receptor Activation Regulation Reporter Role Sodium Dextran Sulfate Stimulus Testing Tissues Toxic Environmental Substances Transcriptional Regulation Xenobiotics base cell type cytokine dextran sulfate sodium induced colitis dietary enteric infection epithelial injury experimental study gastrointestinal epithelium gut microbiota human disease inflammatory disease of the intestine insight microbial microbiota novel novel therapeutics pathogen receptor receptor expression response sensor small molecule tool transcription factor transcriptome

项目摘要

Project Summary/Abstract: Innate lymphoid cells (ILCs) represent an emerging family of cell types that express signature transcription factors, including T-bet+ Eomes+ natural killer (NK) cells, T-bet+ Eomes– type 1 ILCs (ILC1), Gata3+ type 2 ILCs (ILC2), and RORgt+ type 3 ILCs (ILC3). ILCs are abundantly present in mucosal tissues (e.g., lung and gut) at the interface of host-environment interactions. ILC1, ILC2, and ILC3 can readily respond to external stimuli (microbes or dietary components) and produce effector cytokines that mirror their adaptive immune counterparts, Th1, Th2, and Th17/22 cells, respectively. Molecular mechanisms underlying the development and function of ILCs are poorly understood. The aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor, best known to mediate the effects of xenobiotic environmental toxins and endogenous microbial and dietary metabolites. We and others have shown that Ahr is required for ILC3 maintenance and function. Our preliminary data revealed tissue-specific expression of Ahr in ILCs and differential regulation of ILC differentiation and function by Ahr in the gut. We hypothesize that Ahr regulates the ILC2-ILC3 balance in the gut, thus impacting intestinal inflammation and immunity. Specifically, we will investigate 1) the regulation of Ahr expression in ILCs, 2) the molecular mechanism(s) by which Ahr regulates the ILC2-ILC3 balance in the gut, and 3) the functional role of Ahr in regulation of ILCs in DSS-induced gut injury. These experiments will offer an opportunity to elucidate environmental impacts on gut inflammation and immunity via the Ahr-mediated pathway. Our study will provide novel cellular and molecular insights into the development and function of ILCs regulated by Ahr in a tissue- and cell-specific manner. Since Ahr is a ligand-dependent transcription factor and its activity can be regulated by small molecules, modulating Ahr expression and/or function in ILCs may represent a new paradigm for human disease treatment or prevention (e.g., inflammatory bowel disease, enteric infections, and allergic diseases).

项目摘要/摘要：先天淋巴样细胞 (ILC) 代表了表达特征转录的新兴细胞类型家族因子，包括 T-bet+ Eomes+ 自然杀伤 (NK) 细胞、T-bet+ Eomes– 1 型 ILC (ILC1)、Gata3+ 2 型 ILC (ILC2) 和 RORgt+ 3 型 ILC (ILC3) 大量存在于粘膜组织（例如肺和肠道）中。 ILC1、ILC2 和 ILC3 可以轻松响应外部刺激。（微生物或饮食成分）并产生反映其适应性免疫系统的效应细胞因子分别为 Th1、Th2 和 Th17/22 细胞的发育分子机制。 ILC 的功能和功能尚不清楚。芳烃受体 (Ahr) 是一种配体依赖性受体。转录因子，最著名的是介导外源性环境毒素和内源性毒素的影响我们和其他人已经证明 Ahr 是 ILC3 维持和维持所必需的。我们的初步数据揭示了 Ahr 在 ILC 中的组织特异性表达和差异调节。 Ahr 在肠道中的 ILC 分化和功能我们认为 Ahr 调节 ILC2-ILC3 平衡。肠道，从而影响肠道炎症和免疫力具体来说，我们将研究1）调节。 ILC 中 Ahr 表达的影响，2）Ahr 调节 ILC2-ILC3 平衡的分子机制肠道，3) Ahr 在 DSS 诱导的肠道损伤中调节 ILC 的功能作用。提供了一个机会，通过 Ahr 介导的机制来阐明环境对肠道炎症和免疫的影响我们的研究将为 ILC 的发育和功能提供新的细胞和分子见解。由于 Ahr 是配体依赖性转录因子，并且以组织和细胞特异性方式受 Ahr 调节。其活性可以通过小分子调节，调节 ILC 中的 Ahr 表达和/或功能可能代表了人类疾病治疗或预防的新范例（例如炎症性肠病、肠道感染、过敏性疾病）。