EPITHELIAL AND INNATE SENSORS OF THE MICROBIOTA IN IBD
IBD 微生物群的上皮细胞和先天传感器
基本信息
- 批准号:6959577
- 负责人:
- 金额:$ 22.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-04-01 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:P glycoproteinbiological signal transductiondisease /disorder modelgastrointestinal epitheliumgastrointestinal functiongene expressionhost organism interactionimmune responseinflammatory bowel diseaseslaboratory mousemucosal immunityprostaglandin Eprostaglandin endoperoxide synthaseprotein structure functionreceptor expressiontissue /cell culturetoll like receptor
项目摘要
Inflammatory bowel diseases (IBD) are characterized by chronic intestinal inflammation. This persistent inflammation is the result of a poorly controlled mucosal immune response to normal intestinal microbiota. The mechanisms that initiate this aberrant response are not well elucidated; however, one possibility is that a change in the intestinal epithelial barrier results in increased systemic exposure to microbial products. The P-glycoprotein-deficient mouse is a unique model of colitis secondary to the altered function of a membrane hydrophobic pump. Our preliminary findings indicate that this P-glycoprotein-deficient model has an increase in colonic epithelial permeability, as well as a change in the sensitivity of toll-like receptors (TLRs) to bacterial products. We hypothesize that the loss of the intestinal epithelial pump, P-glycoprotein, alters the epithelial barrier and consequently the epithelial sensing of the microbiota by enhancing the ability of microbial products to interact with their specific TLRs. Our hypothesis includes the
concept that in the normal intestine, expression of P-glycoprotein is maintained through the function of epithelial TLR9 and/or cyclooxygenase-2 (COX-2). TLR9 signaling induces COX-2 expression, COX-2 allows for PGE2 to dampen immune responses and upregulate P-glycoprotein expression, and P-glycoprotein functions to pump out toxic xenobiotics, maintain epithelial integrity, and maintain function of regulatory cells. In order to elucidate the relationships between epithelial membrane pumps, microbial sensors, and IBD we propose to: 1) determine the role of P-glycoprotein in the maintenance of intestinal epithelial barrier functions and in the composition and function of the mucosal immune system; 2) characterize the role of P-glycoprotein in the altered expression of TLRs and increased sensitivity to TLR-ligands
seen in intestinal inflammation; and 3) investigate the contribution of TLR9 and COX-2 in the
maintenance of intestinal epithelial barrier function and intestinal homeostasis. These studies will utilize both in vivo models of IBD, as well as in vitro primary and continuous epithelial cell culture systems. The understanding of the basic mechanisms by which the host maintains intestinal homeostasis and barrier integrity will lay the foundation for future studies on the regulation of the inflammatory response and the design of therapies for human IBD.
炎症性肠病(IBD)以慢性肠道炎症为特征。这种持续性炎症是对正常肠道微生物区系控制不良的黏膜免疫反应的结果。启动这种异常反应的机制尚未很好地阐明;然而,一种可能性是肠道上皮屏障的改变导致全身暴露于微生物产品的增加。P-糖蛋白缺陷小鼠是一种独特的结肠炎模型,继发于膜疏水性泵功能的改变。我们的初步发现表明,这种P-糖蛋白缺乏的模型具有结肠上皮通透性增加,以及Toll样受体(TLRs)对细菌产物的敏感性的变化。我们假设,肠道上皮泵P-糖蛋白的丧失,通过增强微生物产品与其特定TLR相互作用的能力,改变了上皮屏障,从而改变了微生物区系的上皮感觉。我们的假设包括
在正常肠道中,P-糖蛋白的表达是通过上皮细胞TLR9和/或环氧合酶-2(COX-2)的作用来维持的。TLR9信号诱导COX-2的表达,COX-2使PGE2抑制免疫反应并上调P-糖蛋白的表达,P-糖蛋白的功能是排出有毒的外源性物质,维持上皮完整性,维持调节细胞的功能。为了阐明上皮膜泵、微生物感受器和IBD之间的关系,我们建议:1)确定P-糖蛋白在维持肠上皮屏障功能和粘膜免疫系统的组成和功能中的作用;2)表征P-糖蛋白在TLRs表达改变和对TLR-配体的敏感性增加中的作用
3)研究TLR9和COX-2在肠道炎症中的作用。
维持肠上皮屏障功能和肠道内环境平衡。这些研究将利用IBD的体内模型,以及体外原代和连续上皮细胞培养系统。对宿主维持肠道内环境稳定和屏障完整性的基本机制的了解,将为今后研究炎性反应的调节和人类IBD治疗方案的设计奠定基础。
项目成果
期刊论文数量(0)
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Robinna Gail Lorenz其他文献
Robinna Gail Lorenz的其他文献
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{{ truncateString('Robinna Gail Lorenz', 18)}}的其他基金
Preparation for Graduate and Medical Education(PreGAME)Program
研究生和医学教育准备(PreGAME)计划
- 批准号:
9257456 - 财政年份:2014
- 资助金额:
$ 22.62万 - 项目类别:
Preparation for Graduate and Medical Education(PreGAME)Program
研究生和医学教育准备(PreGAME)计划
- 批准号:
8829327 - 财政年份:2014
- 资助金额:
$ 22.62万 - 项目类别:
Preparation for Graduate and Medical Education(PreGAME)Program
研究生和医学教育准备(PreGAME)计划
- 批准号:
8612197 - 财政年份:2014
- 资助金额:
$ 22.62万 - 项目类别:
EPITHELIAL AND INNATE SENSORS OF THE MICROBIOTA IN IBD
IBD 微生物群的上皮细胞和先天传感器
- 批准号:
7486782 - 财政年份:2007
- 资助金额:
$ 22.62万 - 项目类别:
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