Immune Modulation of Intestinal Goblet Cell Responses

肠道杯状细胞反应的免疫调节

• 批准号: 7350905
• 负责人: MEI-LUN WANG
• 金额: $ 13.33万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7350905
• 关键词: Adjuvant; Affect; Binding; CD4 Positive T Lymphocytes; Cell Line; Cell physiology; Cellular Morphology; Colon; Consensus; DNA; DNA Binding; Development; Disease; Dose; Effector Cell; Elements; Environment; Family; Gene Expression; Genes; Genus Cola; Goblet Cells; Host Defense; Hyperplasia; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Inflammatory Response; Interferons; Interleukin-13; Interleukin-4; Intestines; Lead; Mediating; Mentors; Modeling; Morbidity - disease rate; Mus; NF-kappa B; Nematoda; Nematode infections; Parasitic infection; Parasitic nematode; Pathway interactions; Phenotype; Physicians; Play; Population; Promoter Regions; Protein Overexpression; Proteins; Range; Regulation; Reporter Genes; Research; Research Personnel; Resistance; Resources; Role; SCID Mice; Scientist; Signal Pathway; Signal Transduction; Site; Stimulus; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Time; Transcription Coactivator; Transducers; Trichuris; Work; cell type; cis acting element; commensal microbes; cytokine; enteric pathogen; immunoregulation; in vivo; inhibitor/antagonist; insight; mortality; mutant; novel; prevent; programs; promoter; response; synergism; transcription factor

DESCRIPTION (provided by applicant): Intestinal nematode infections are a major cause of morbidity and mortality throughout the world, affecting up to one quarter of the world's population. I describe a unique goblet cell-specific protein called RELMB which is secreted apically into the intestinal lumen, where it plays a novel role in vertebrate resistance to intestinal parasitic infection. It has been established that Th2-mediated intestinal inflammatory responses, typified by host responses to nematode infection, lead to goblet cell hyperplasia. Very little is currently known about the mechanisms by which the host immune system regulates the development of the goblet cell-specific genes in response to nematode infection. Using RELMB as a model, I show that goblet cell development in the intestinal tract is regulated by the intestine-specific transcription factor, Cdx2. I further demonstrate that RELMB expression can be induced by bacterial colonization in the absence of the acquired immune system, and that highest levels of RELMa expression are induced by intestinal nematode infection. My overall hypothesis is that basal intestine-specific activation of [sic] the RELMB promoter requires the Cdx family of transcription factors, and that TLRs and their downstream signaling pathways synergize with Th2-mediated pathways to optimally activate goblet cell responses to parasitic infections. 3 Specific Aims will be pursued: 1) The functional importance of NFkB and Stat6 cis-acting elements within the RELM-B promoter will be studied in vitro, and synergism with Cdx2 will be investigated. 2) A Trichuris muris model of murine nematode infection will be studied in mice with targeted deletions of MyD88, NFkB1, and Stat6 to determine the effect on RELMa expression. 3) Adoptive T cell transfer studies will be performed in T. muris infected SCID mice to determine the role of CD4+ T cells and Th2 cytokines in RELMB expression and nematode expulsion. My results will provide insight into the interactions between host innate and adaptive immunity, and will elucidate mechanisms by which goblet cells function as immune effector cells in the colon.

描述（由申请人提供）：肠道线虫感染是全世界发病率和死亡率的主要原因，影响到世界上多达四分之一的人口。我描述了一种独特的杯状细胞特异性蛋白质，称为RELMB，它分泌到肠腔的顶端，在脊椎动物抵抗肠道寄生虫感染中起着新的作用。已经确定th2介导的肠道炎症反应，以宿主对线虫感染的反应为典型，导致杯状细胞增生。目前对宿主免疫系统如何调节杯状细胞特异性基因的发育以应对线虫感染的机制知之甚少。我以RELMB为模型，证明了肠道杯状细胞的发育受肠道特异性转录因子Cdx2的调控。我进一步证明，在没有获得性免疫系统的情况下，细菌定植可以诱导RELMB的表达，并且肠线虫感染诱导RELMa的最高表达水平。我的总体假设是，RELMB启动子的基础肠道特异性激活需要Cdx家族转录因子，tlr及其下游信号通路与th2介导的途径协同作用，以最佳方式激活杯状细胞对寄生虫感染的反应。具体目标：1)将在体外研究NFkB和Stat6顺式作用元件在RELM-B启动子中的功能重要性，并研究与Cdx2的协同作用。2)将在MyD88、NFkB1和Stat6靶向缺失的小鼠中研究鼠毛线虫感染模型，以确定对RELMa表达的影响。3)将在鼠T感染的SCID小鼠中进行过继T细胞转移研究，以确定CD4+ T细胞和Th2细胞因子在RELMB表达和线虫驱逐中的作用。我的研究结果将为宿主先天免疫和适应性免疫之间的相互作用提供见解，并将阐明杯状细胞在结肠中作为免疫效应细胞的机制。