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: 6959577
• 负责人: Robinna Gail Lorenz
• 金额: $ 22.62万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/6959577
• 关键词: P glycoprotein; biological signal transduction; disease /disorder model; gastrointestinal epithelium; gastrointestinal function; gene expression; host organism interaction; immune response; inflammatory bowel diseases; laboratory mouse; mucosal immunity; prostaglandin E; prostaglandin endoperoxide synthase; protein structure function; receptor expression; tissue /cell culture; toll like receptor

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）的特征是慢性肠道炎症。这种持续性炎症是对正常肠道微生物群的粘膜免疫反应控制不佳的结果。引发这种异常反应的机制尚未得到很好的阐明。然而，一种可能性是肠上皮屏障的变化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，继发于膜疏水泵功能的改变。我们的初步研究结果表明，这种 P-糖蛋白缺陷模型的结肠上皮通透性增加，并且 Toll 样受体 (TLR) 对细菌产物的敏感性发生变化。我们假设肠上皮泵 P-糖蛋白的丧失会改变上皮屏障，从而通过增强微生物产物与其特定 TLR 相互作用的能力来改变上皮对微生物群的感知。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 TLR9 和/或环氧合酶-2 (COX-2) 的功能来维持的。 TLR9 信号传导诱导 COX-2 表达，COX-2 允许 PGE2 抑制免疫反应并上调 P-糖蛋白表达，P-糖蛋白发挥排出有毒异生物质、维持上皮完整性和调节细胞功能的作用。为了阐明上皮膜泵、微生物传感器和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以及粘膜免疫系统的组成和功能中的作用； 2) 表征 P-糖蛋白在 TLR 表达改变和对 TLR 配体敏感性增加中的作用 见于肠道炎症； 3) 研究 TLR9 和 COX-2 在 维持肠上皮屏障功能和肠道稳态​​。这些研究将利用 IBD 体内模型以及体外原代和连续上皮细胞培养系统。了解宿主维持肠道稳态和屏障完整性的基本机制将为未来炎症反应调节的研究和人类IBD疗法的设计奠定基础。