Immune Modulation of Intestinal Goblet Cell Responses

肠道杯状细胞反应的免疫调节

• 批准号: 7574377
• 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/7574377
• 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; 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; Proteins; 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; overexpression; 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（由申请方提供）：肠道线虫感染是全世界发病率和死亡率的主要原因，影响了多达四分之一的世界人口。我描述了一种独特的杯状细胞特异性蛋白质称为ESTMB，它分泌到肠腔的顶端，在那里它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，以宿主对线虫感染的反应为代表的Th2介导的肠道炎症反应导致杯状细胞增生。目前对宿主免疫系统调节杯状细胞特异性基因响应线虫感染的机制知之甚少。使用ESTMB作为模型，我表明，在肠道杯状细胞的发展是由甜菜碱特异性转录因子，Cdx2。我进一步证明，在缺乏获得性免疫系统的情况下，细菌定植可以诱导ESTIMB表达，并且肠道线虫感染诱导了最高水平的ESTIMA表达。我的总体假设是，基础的精氨酸特异性激活的[原文如此]的CDMB启动子需要Cdx家族的转录因子，和TLR和它们的下游信号通路协同与Th2介导的途径，以最佳激活杯状细胞反应寄生虫感染。3.具体目标：1）体外研究NFkB和Stat6顺式作用元件的功能重要性，并研究其与Cdx2的协同作用。2)将在MyD88、NFkB1和Stat6靶向缺失的小鼠中研究鼠线虫感染的鼠鞭虫模型，以确定对MyD88、NFkB1和Stat6表达的影响。3)将在T.小鼠感染的SCID小鼠，以确定CD4+ T细胞和Th2细胞因子在CD4MB表达和线虫排出中的作用。我的研究结果将提供深入了解宿主先天免疫和适应性免疫之间的相互作用，并将阐明杯状细胞在结肠中作为免疫效应细胞发挥作用的机制。