Role of RORgt+ (note: g: is gamma symbol) lymphocytes in Gut Tissue Homeostasis

RORgt（注：g：是伽玛符号）淋巴细胞在肠道组织稳态中的作用

• 批准号: 10456906
• 负责人: Liang Zhou
• 金额: $ 56.05万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456906
• 关键词: Ablation; Adoptive Transfer; Affect; Anabolism; Anaerobic Bacteria; Antibiotic Therapy; Cell Compartmentation; Cell Differentiation process; Cell Maintenance; Cell Proliferation; Cell physiology; Cells; Cellular Metabolic Process; Coculture Techniques; DNA biosynthesis; Data; Development; Disease; Effector Cell; Environment; Epigenetic Process; Epithelial Cells; Exhibits; Generations; Genetic; Genetic Transcription; Glycolysis; Helper-Inducer T-Lymphocyte; Histologic; Homeostasis; Immune; Immunity; In Vitro; Individual; Infection; Inflammation; Inflammatory Bowel Diseases; Interleukin-13; Interleukin-17; Interleukin-18; Length; Lymphocyte; Lymphocyte Biology; Lymphocyte Function; Lymphoid Cell; Maintenance; Mediating; Metabolic; Metabolism; Metronidazole; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Mutant Strains Mice; Orphan; Oxidative Phosphorylation; Paper; Pathogenesis; Phenotype; Play; Population; Prevention; Production; Reactive Oxygen Species; Regulation; Respiration; Retinoic Acid Receptor; Role; Small Intestines; System; T-Lymphocyte; Tissues; Tritrichomonas; base; cytokine; enteric infection; experimental study; factor A; gastrointestinal epithelium; glucose metabolism; gut microbiome; helminth infection; human disease; immune function; in vivo; insight; interleukin-22; intestinal homeostasis; intestinal injury; microbiome; mitochondrial metabolism; mtTF1 transcription factor; novel; novel therapeutics; prevent; programs; receptor; transcription factor; transcriptome

Project Summary/Abstract: ILC3s, gdT17 and Th17 cells share common features, e.g., expressing the master transcription factor RORgt and the effector cytokines IL-17A, IL-17F and IL-22, and perform distinct immune functions under different environment context. Our preliminary data suggest that RORgt+ cell-intrinsic deletion of Tfam in Tfamfl/flRorc- cre mice affected RORgt+ gdT17 cells and ILC3s in vivo maintenance and led to small intestinal tissue remodeling via a tuft cell–ILC2 circuit. An emerging concept of mitochondrial control of immunity beyond ATP generation has recently been proposed. Based on the premise and our preliminary data, we hypothesize that that Tfam-mediated mitochondrial respiration in gdT17 cells and ILC3s is pivotal for gdT17/ILC3 cell homeostasis and regulation of small intestine tissue remodeling/metabolic changes and immunity/inflammation. Specifically, we will investigate 1) the role of Tfam in gdT17 and ILC3 lymphocyte maintenance, 2) the role of Tfam in gdT17 cells and/or ILC3s in regulating tuft cell-ILC2 circuit and small intestine tissue remodeling, and 3) the role of Tfam in gdT17 cells and/or ILC3s in regulation of microbiome and small intestinal immunity and inflammation. These experiments will offer an opportunity to elucidate Tfam- mediated mitochondrial respiration in RORgt+ lymphocytes in the small intestine under the steady state and during infection/immunity. Our study will provide novel cellular and molecular insights into the maintenance and function of gdT17 cells and ILC3s regulated by Tfam. Understanding the mechanisms underlying the requirement of Tfam for RORgt+ cells in regulation of small intestine tissue remodeling and immunity may represent a new paradigm for human disease treatment and/or prevention.

项目摘要/摘要： ILC3s、gdT17和Th17细胞有共同的特征，例如表达主转录因子RORgt 而效应细胞因子IL-17A、IL-17F和IL-22在不同的条件下表现出不同的免疫功能。 环境背景。我们的初步数据表明，Tffl/flRorc-中的RORgt+细胞固有的Tfam缺失 CRE小鼠影响RORgT+gdT17细胞和ILC3的体内维持并导致小肠组织 通过簇状细胞-ILC2回路进行重塑。线粒体控制超越三磷酸腺苷免疫的新概念 最近有人提出了发电的建议。根据前提和我们的初步数据，我们假设 TfAM介导的gdT17细胞和ILC3细胞线粒体呼吸对gdT17/ILC3细胞起关键作用 小肠组织重塑/代谢变化的动态平衡与调控 免疫/炎症。具体地说，我们将研究1)Tfam在gdT17和ILC3淋巴细胞中的作用 维持，2)tfam在gdT17细胞和/或ILC3调节簇状细胞中的作用-ILC2回路和小分子 肠组织重塑，以及3)Tfam在gdT17细胞和/或ILC3调节微生物组和/或ILC3中的作用 小肠免疫和炎症。这些实验将提供一个机会来阐明TFAM- 稳态和低氧状态下小肠RORgT~+淋巴细胞介导的线粒体呼吸 在感染/免疫期间。我们的研究将提供新的细胞和分子方面的见解来维持和 Tfam对gdT17细胞和ILC3功能的调节。了解以下机制 Tfam在调节小肠组织重塑和免疫中对RORgt+细胞的需求可能 代表了人类疾病治疗和/或预防的新范例。