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）的特征是慢性肠炎。这种持续性炎症是对正常肠道菌群的粘膜免疫反应不良的结果。启动这种异常反应的机制无法很好地阐明；但是，一种可能性是，肠上皮屏障的变化导致系统性暴露于微生物产物。 P-糖蛋白缺陷型小鼠是膜疏水泵功能改变的结肠炎的独特模型。我们的初步发现表明，这种缺乏蛋白质缺陷蛋白的模型的结肠上皮渗透性有所增加，以及Toll样受体（TLRS）对细菌产物的敏感性的变化。我们假设肠上皮泵的损失通过增强微生物产物与特定TLR相互作用的能力，从而改变了上皮屏障，从而改变了上皮屏障。我们的假设包括 在正常肠道中，通过上皮TLR9和/或环氧酶-2（COX-2）的功能来维持P-糖蛋白的表达。 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，并促进P-糖蛋白功能，以泵出有毒的异生物学，维持上皮完整性，并维持调节细胞的功能。为了阐明上皮膜泵，微生物传感器和IBD之间的关系：1）确定p-糖蛋白在维持肠上皮屏障功能以及在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的表达改变和对TLR配体敏感性提高的作用 在肠道炎症中可见； 3）研究TLR9和COX-2在 维持肠上皮屏障功能和肠内稳态。这些研究将利用IBD的体内模型，以及体外原发性和连续的上皮细胞培养系统。对宿主维持肠道稳态和障碍完整性的基本机制的理解将为未来的炎症反应调节和人类IBD治疗设计的研究奠定基础。