INTESTINAL IMMUNE SYSTEM IN HOST-ENVIRONMENT INTERACTION

总体描述（由申请人提供）： 该计划项目的中心主题是关注决定肠粘膜对肠道微生物和微生物产物的先天性和获得性免疫反应的机制，以及随后的粘膜保护性免疫和炎症反应。这四个相互关联的研究项目专门针对上皮细胞和树突状细胞之间以及树突状细胞和T细胞之间的通讯调节，这发生在粘膜稳态和保护性免疫过程中。模型肠道病原体用于探测新的体内和体外鼠模型系统中的粘膜细胞应答。该项目汇集了来自医学、病理学和神经科学系以及加州大学圣地亚哥分校校园的拉霍亚过敏和免疫学研究所的经验丰富的研究人员。研究人员在细胞和分子粘膜免疫学、粘膜炎症、细胞信号传导和微生物发病机制方面具有重要的专业知识，并有合作互动的记录。第一研究单元研究结肠和小肠中树突状细胞（DC）和上皮细胞对先天性粘膜免疫应答的调节。单元1使用附着和消失的病变诱导肠道病原体和轮状病毒来探测宿主反应，以及粒细胞-巨噬细胞集落刺激因子决定肠道感染结果的机制。研究单位2调查肠粘膜反应，确定对微创肠道病原体的免疫防御，使用贾第虫作为模型原生动物病原体，在没有粘膜炎症的情况下激发强大的保护性免疫。研究单元3研究粘膜佐剂如何克服T调节细胞的耐受诱导作用，并激发效应T细胞免疫应答，重点是霍乱毒素和Th 17分化在体外和体内。研究单元4是该计划的新成员，其更新申请研究了类维生素A通过其对DC和T细胞的活性确定正常粘膜稳态和保护性免疫之间平衡的机制。研究项目由四个核心支持：小鼠模型核心，组织学核心，成像和细胞分选核心和管理核心。

DESCRIPTION, OVERALL (provided by applicant): The central theme of the Program Project Is focused on mechanisms that determine innate and acquired immune responses in the intestinal mucosa to enteric microbes and microbial products, and the consequent mucosal protective immune and inflammatory responses. The four interrelated research projects specifically address the regulation of communication between epithelial cells and dendritic cells, and between dendritic cells and T cells, which takes place during mucosal homeostasis and protective immunity. Model enteric pathogens are used to probe mucosal cellular responses in novel in vivo and in vitro murine model systems. The program brings together experienced investigators from the Departments of Medicine, Pathology, and Neurosciences and the UCSD campus based La Jolla Institute for Allergy and Immunology. The investigators have a record of significant expertise in cellular and molecular mucosal immunology, mucosal inflammation, cell signaling and microbial pathogenesis, and a record of collaborative interactions. Research Unit 1 investigates the regulation of innate mucosal immune responses by dendritic cells (DC) and epithelial cells in the colon and small intestine. Unit 1 uses an attaching and effacing lesion-inducing enteric pathogen and rotavirus to probe the host response, and the mechanisms by which granulocyte-macrophage colony stimulating factor determines the outcome of enteric infection. Research Unit 2 investigates intestinal mucosal responses that determine immune defenses against minimally invasive enteric pathogens, using Giardia as a model protozoan pathogen that elicits strong protective immunity in the absence of mucosal inflammation. Research Unit 3 investigates how mucosal adjuvants override the tolerance-inducing effects of T regulatory cells and provoke effector T cell immune responses, with a focus on cholera toxin and Th17 differentiation in vitro and in vivo. Research Unit 4, which is new to the Program with the renewal application, investigates mechanisms by which retinoids determine the balance between normal mucosal homeostasis and protective immunity through their activity on DC and T cells. The research projects are supported by four Cores: a Mouse Model Core, a Histopathology Core, an Imaging and Cell Sorting Core and an Administrative Core.