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
• 负责人: Robinna Gail Lorenz
• 金额: $ 22.45万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486782
• 关键词: Animal Model; Antigen-Presenting Cells; Antigens; Appearance; Bacteria; Cell Culture System; Cell physiology; Cells; Chronic; Colitis; Colon; Condition; Coupled; Defect; Development; Dinoprostone; Distal; Dominant-Negative Mutation; E-Cadherin; Enteral; Epithelial; Epithelial Cells; Equilibrium; Exposure to; Feedback; Flagellin; Foundations; Functional disorder; Future; Genetic Polymorphism; Genetically Engineered Mouse; Genus Cola; Glycoproteins; Grant; Histologic; Homeostasis; Host Defense Mechanism; Human; Human Volunteers; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-10; Intestines; Intraepithelial T-Lymphocyte; Knowledge; Laboratories; Lead; Ligands; Lipopolysaccharides; Lymphocyte; Maintenance; Membrane; Modeling; Mucosal Immune Responses; Multidrug Resistance Gene; Mus; N-Cadherin; P-Glycoprotein; P-Glycoproteins; Permeability; Population; Prevention Protocols; Pump; Regulation; Regulatory T-Lymphocyte; Risk; Role; Secondary to; Signal Transduction; Small Intestines; Surface; T-Lymphocyte; TLR4 gene; Tight Junctions; Toll-like receptors; Ulcerative Colitis; Xenobiotics; concept; cyclooxygenase 2; design; experience; gastrointestinal epithelium; gastrointestinal system; germ free condition; improved; in vivo Model; intraepithelial; microbial; pathogen; programs; receptor; response; sensor; therapy design; tool

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。这种持续的炎症是对正常肠道微生物群的黏膜免疫反应控制不良的结果。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改变导致全身暴露于微生物产物的增加。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改变。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增加，以及toll样受体（TLRs）对细菌产物敏感性的变化。我们假设肠上皮泵p -糖蛋白的缺失，通过增强微生物产物与其特异性TLRs相互作用的能力，改变了上皮屏障，从而改变了微生物群的上皮感知。我们的假设包括