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

基本信息

批准号：
8737236
负责人：
Ryan B Sartor
金额：
$ 151.55万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/8737236
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 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 imaging macrophage microbial microbiome microorganism interaction neutrophil nonalcoholic steatohepatitis novel prevent programs receptor skills

项目摘要

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）：宿主先天免疫系统和肠道微生物群之间的相互作用是特发性人类炎症性肠病（IBD）发病机制中的近端事件。解决 IBD 的发病机制并最终治愈和预防这些慢性、衰弱性疾病，取决于使用实验模型和人体系统来更好地了解先天免疫和肠道微生物之间的功能相互作用，从而决定粘膜组织中效应 T 细胞亚群与调节性 T 细胞亚群的分化和激活。我们假设共生微生物群的子集优先激活保护性而非破坏性的先天信号通路，这些信号通路综合激活粘膜先天细胞和抗原呈递细胞，分泌细胞因子，促进调节性 T 细胞与效应 T 细胞的反应。这些相互作用的细菌激活的先天和适应性途径介导稳态与效应免疫反应，并且可以被操纵用于治疗目的。这一假设将通过六名完全整合的研究人员的协同努力得到解决，他们在先天免疫和宿主-微生物群相互作用方面具有互补的专业知识，并由两个高度利用的核心推动。项目1（Jenny Ting）：“肠道炎症中的NOD样受体”。项目 2 (Balfour Sartor)：“IL-10 在 APC 调节共生细菌的保护性 T 细胞与致病性 T 细胞反应中的作用”。项目 3 (Scott Plevy)：“肠道炎症中肠道微生物群对巨噬细胞 IL-10 和 IL-12 的调节”。项目 4（约翰·罗尔斯）：“全身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，这两个核心已经促进了合作研究。核心 A：知生和转基因啮齿动物和斑马鱼核心（核心联合主任，Sartor 博士和 Rawls 博士）。核心 B：人体组织和基因组学核心（联合主任：Scott Plevy 博士、Hans Herfarth 和 Shehzad Sheikh）。在 Cores 的协助下，研究人员准备加速了解先天免疫系统如何与肠道微生物群在健康和疾病中相互作用。这些知识可能会对 IBD 以及因先天免疫与肠道微生物群相互作用失调而导致的众多疾病产生重大的公共卫生影响。