EPITHELIAL AND INNATE SENSORS OF THE MICROBIOTA IN IBD

炎症性肠病（IBD）的特征在于慢性肠道炎症。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良的结果。启动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微生物产物的全身暴露增加。P-糖蛋白缺陷小鼠是继发于膜疏水泵功能改变的结肠炎的独特模型。我们的初步研究结果表明，这种P-糖蛋白缺陷模型具有结肠上皮通透性的增加，以及Toll样受体（TLR）对细菌产物的敏感性的变化。我们假设，肠上皮泵，P-糖蛋白的损失，改变了上皮屏障，从而通过增强微生物产物与其特异性TLR相互作用的能力，改变了上皮对微生物群的感知。我们的假设包括 在正常肠中，P-糖蛋白的表达通过上皮细胞TLR 9和/或环氧合酶-2（考克斯-2）的功能维持。TLR 9信号传导诱导考克斯-2表达，考克斯-2允许PGE 2抑制免疫应答并上调P-糖蛋白表达，并且P-糖蛋白功能是泵出有毒的外源性物质，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，我们提出：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-糖蛋白在改变TLR表达和增加对TLR配体的敏感性中的作用 研究TLR 9和考克斯-2在肠道炎症中的作用。 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代和连续上皮细胞培养系统。对宿主维持肠道内稳态和屏障完整性的基本机制的理解将为未来研究炎症反应的调节和人类IBD治疗的设计奠定基础。

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.