The molecular basis of host-microbiota interactions

宿主-微生物群相互作用的分子基础

基本信息

批准号：
9257675
负责人：
Nicholas J. Bessman
金额：
$ 6.2万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2017-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9257675
关键词：
Achromobacter Address Alcaligenes Arginine Bacteria Betaproteobacteria Bordetella Cardiovascular Diseases Cell physiology Cellular Metabolic Process Chronic Chronic Disease Coculture Techniques Data Dendritic Cell Pathway Dendritic Cells Diabetes Mellitus Disease Future Genes Genetic Goals Heart Diseases Homeostasis Human Immune Immune response Immune system Immunity In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Innate Immune Response Innate Immune System Interleukin-1 beta Interleukin-10 Intestines Intrinsic factor Iron Laboratories Lead Lymphoid Cell Lymphoid Follicle Lymphoid Tissue Malignant Neoplasms Mammals Mesentery Metabolism Modeling Molecular Mus Nitric Oxide Nitric Oxide Pathway Ochrobactrum Pathogenesis Pathway interactions Physiology Population Production Publishing Recombinant Cytokines Recovery Reporting Role Structure of aggregated lymphoid follicle of small intestine Symbiosis Testing Therapeutic Tissue Expansion Tissues arginase commensal microbes cytokine gut microbiota hepcidin human disease in vivo in vivo Model interleukin-23 loss of function lymph nodes member microbiota mouse model nonhuman primate novel novel therapeutics response tissue repair

项目摘要

PROJECT SUMMARY Dysregulation of the intestinal microbiota and the human immune system is thought to contribute to chronic diseases such as inflammatory bowel disease, heart disease, diabetes, and cancer. A better understanding of the interactions between the microbiota and the host immune system should highlight novel therapeutic strategies for these chronic diseases, including therapies directly targeting the microbiota rather than the host. Recent studies have shown that a subset of the microbiota colonizes healthy human, non-human primate, and mouse lymphoid tissues. These bacteria, termed lymphoid tissue-resident commensals or LRCs, elicit unique innate immune responses, and protect against intestinal inflammation. However, the molecular basis of LRC colonization of lymphoid tissues, and LRC-elicited innate immune responses, remains unclear. Preliminary data in this proposal suggests that LRCs may suppress host nitric oxide responses in dendritic cells using a conserved bacterial arginase. Aim 1 will utilize in vitro and in vivo models of LRC colonization to interrogate the interaction between LRC arginases and the host innate immune system. Additionally, preliminary studies suggest that host iron transport may actively contribute to both LRC colonization and intestinal inflammation. Aim 2 will utilize in vitro and in vivo models of LRC colonization, along with novel murine models with modified iron transport, to investigate the connection between LRC colonization, host iron transport, and inflammation. Collectively, these two aims will crucially define the molecular basis by which LRCs colonize mammalian hosts and modulate intestinal inflammation.

项目概要肠道微生物群和人体免疫系统的失调被认为会导致慢性疾病炎症性肠病、心脏病、糖尿病和癌症等疾病。更好地理解微生物群和宿主免疫系统之间的相互作用应该突出新的治疗方法针对这些慢性疾病的策略，包括直接针对微生物群而不是宿主的疗法。最近的研究表明，微生物群的一个子集定植于健康人类、非人类灵长类动物和小鼠淋巴组织。这些细菌被称为淋巴组织驻留共生菌或 LRC，可引发独特的先天免疫反应，并防止肠道炎症。然而，LRC 的分子基础淋巴组织的定植以及 LRC 引发的先天免疫反应仍不清楚。初步的该提案中的数据表明，LRC 可以使用以下方法抑制树突状细胞中的宿主一氧化氮反应：保守的细菌精氨酸酶。目标 1 将利用 LRC 定植的体外和体内模型来探究 LRC 精氨酸酶与宿主先天免疫系统之间的相互作用。此外，初步研究表明宿主铁转运可能积极促进 LRC 定植和肠道炎症。目标 2 将利用 LRC 定植的体外和体内模型，以及经过改良的新型小鼠模型铁转运，研究 LRC 定植、宿主铁转运和炎症之间的联系。总的来说，这两个目标将至关重要地定义 LRC 定植哺乳动物宿主的分子基础并调节肠道炎症。