The molecular basis of host-microbiota interactions

宿主-微生物群相互作用的分子基础

• 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
• 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

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.

项目摘要 肠道微生物群和人体免疫系统的失调被认为有助于慢性炎症。 炎症性肠道疾病、心脏病、糖尿病和癌症等疾病。更好地了解 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， 这些慢性疾病的治疗策略，包括直接针对微生物群而不是宿主的治疗。 最近的研究表明，微生物群的一个子集在健康的人类、非人类灵长类动物和哺乳动物中定植。 小鼠淋巴组织。这些细菌被称为淋巴组织驻留的细菌或LRC， 天然免疫反应，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 该提案中的数据表明，LRC可能通过抑制树突细胞中的宿主一氧化氮反应， 保守的细菌淀粉酶。目的1将利用LRC定殖的体外和体内模型来询问 LRC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地促进LRC定植和肠道炎症。 目的2将利用LRC定殖的体外和体内模型，沿着新的小鼠模型， 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，这两个目标将决定性地定义LRC在哺乳动物宿主中定殖的分子基础 调节肠道炎症