Host innate immune-microbial interactions and intestinal inflammation

宿主先天免疫-微生物相互作用和肠道炎症

• 批准号: 8552303
• 负责人: Ryan B Sartor
• 金额: $ 152.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8552303
• 关键词: Address; Animal Model; Antigen-Presenting Cells; Autoimmunity; Biopsy; Cells; Chronic; Clinical; Clinical Trials; Colitis; Collaborations; Colon Carcinoma; Complement; Cytokine Gene; Diabetes Mellitus; Disease; Ecology; Enteral; Enterobacteriaceae; Etiology; Event; Experimental Models; Gene Expression; Gene Targeting; Genetic; Genome; Genomics; Gnotobiotic; Goals; Health; Homeostasis; Human; Human Resources; Image; Immune; Immune response; Immune system; Immunologics; Immunologist; Immunology; Infection; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-10; Interleukin-12; Intestines; Knowledge; Label; Leukocytes; Mediating; Metabolic syndrome; Microbe; Modeling; Molecular Biology; Mucous Membrane; Mus; Natural Immunity; Obesity; Pathogenesis; Pathway interactions; Public Health; RNA; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Resected; Resolution; Rodent; Role; Science; Signal Pathway; Source; System; T cell response; T-Lymphocyte Subsets; Therapeutic; Tissues; Transcriptional Regulation; Transgenic Organisms; Zebrafish; chemical genetics; commensal microbes; cytokine; experience; human disease; human tissue; in vivo; macrophage; microbial; microbiome; microorganism interaction; neutrophil; nonalcoholic steatohepatitis; novel; prevent; programs; receptor; skills

DESCRIPTION (provided by applicant): Interactions between the host innate immune system and the enteric microbiota are proximal events in the pathogenesis of the idiopathic human inflammatory bowel diseases (IBD). Solving the pathogenesis of IBD and ultimately curing and preventing these chronic, debilitating conditions depends on using experimental models and human systems to better understand functional interactions between innate immunity and enteric microbes that determine differentiation and activation of effector vs. regulatory T cell subsets in mucosal tissues. We hypothesize that subsets of the commensal microbiota preferentially activate protective vs. destructive innate signaling pathways that integratively activate mucosal innate and antigen presenting cells to secrete cytokines that promote regulatory vs. effector T cell responses. These interacting bacterially- activated innate and adaptive pathways mediate homeostatic vs. effector immune responses and can be manipulated for therapeutic purposes. This hypothesis will be addressed through synergistic efforts of six fully integrated investigators with complementary expertise in innate immunity and host-microbiota interactions, facilitated by two highly utilized cores. Project 1 (Jenny Ting): "NOD-like receptors in intestinal inflammation". Project 2 (Balfour Sartor): "Role of IL-10 in APC regulation of protective vs. pathogenic T cell responses to commensal bacteria". Project 3 (Scott Plevy): "Macrophage IL-10 and IL-12 regulation by the enteric microbiota in intestinal inflammation ". Project 4 (John Rawls): "Microbial regulation of systemic neutrophil function". The Project Leaders will be supported by two highly interactive cores that have already facilitated collaborative research. Core A: Gnotobiotic and Transgenic Rodent and Zebrafish Core (Core Co- Directors, Drs. Sartor and Rawls). Core B: Human Tissue and Genomics Core (Co-Directors, Drs. Scott Plevy, Hans Herfarth and Shehzad Sheikh). The investigators, facilitated by Cores, are poised to accelerate the understanding of how the innate immune system interacts with the enteric microbiota in health and disease. This knowledge could have a major public health impact upon IBD and the numerous disorders that result from dysregulated innate immune interactions with enteric microbiota.

描述（由申请人提供）：宿主先天免疫系统与肠菌群之间的相互作用是特发性人体炎症性肠病（IBD）的发病机理中的近端事件。解决IBD的发病机理，并最终固化并防止这些慢性，使人衰弱的条件取决于使用实验模型和人类系统，以更好地理解先天免疫与确定粘膜组织中效应子与调节性T细胞的分化和激活的肠子微生物之间的功能相互作用。我们假设共生微生物群的子集优先激活保护性与破坏性的先天信号传导途径，这些途径综合激活了粘膜先天和抗原呈递细胞，以分泌细胞因子，从而促进调节性和效应的T细胞反应。这些相互作用的细菌活化的先天和适应性途径介导稳态和效应免疫反应，并且可以用于治疗目的。这一假设将通过六位完全综合的研究人员的协同努力来解决，这些研究人员在先天免疫和宿主 - 微生物群相互作用方面具有互补的专业知识，这是由两个高度利用的核心促进的。项目1（Jenny Ting）：“肠炎中的点头样受体”。项目2（Balfour Sartor）：“ IL-10在APC调节保护性T细胞对共生细菌的反应中的作用”。项目3（斯科特·普莱维（Scott Plevy））：“肠道炎症中肠菌群的巨噬细胞IL-10和IL-12调节”。项目4（John Rawls）：“全身性中性粒细胞功能的微生物调节”。项目负责人将得到两个高度互动的核心的支持，这些核心已经促进了协作研究。核心A：Gnotobiotic和转基因啮齿动物和斑马鱼核心（核心董事，萨托尔和罗尔斯）。核心B：人体组织和基因组学核心（联合导演，Scott Plevy博士，Hans Herfarth和Shehzad Sheikh）。由核心促进的研究人员有望加速对先天免疫系统如何与健康和疾病中肠子菌群相互作用的理解。这些知识可能会对IBD产生重大的公共卫生影响，以及与肠子微生物群的先天免疫相互作用失调所致的众多疾病。