PATHOGENS, PROBIOTICS AND THE EPITHELIUM IN COLITIS

结肠炎中的病原体、益生菌和上皮细胞

• 批准号: 6989790
• 负责人: Kim Elaine Barrett
• 金额: $ 26.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989790
• 关键词: PATHOGENS; PROBIOTICS; EPITHELIUM; COLITIS

DESCRIPTION (provided by applicant): Our long-term goal is to understand intestinal epithelial transport and barrier function. Substantial evidence suggests that these critical functions are altered in the setting of inflammatory bowel disease and other intestinal disorders. Moreover, we hypothesize that inflammatory bowel disease results when intestinal barrier function is inadequate to exclude luminal factors, thereby resulting in immune stimulation and a vicious cycle of inflammation and injury that further compromises transport and barrier homeostasis. We will also test the specific hypothesis that probiotic microorganisms exert protective effects on intestinal epithelial cells under both basal conditions and when they are compromised by pathogenic microorganisms or other injurious insults. We will test our hypotheses by addressing two specific aims. In the first, we will examine whether barrier and transport functions are altered in a mouse model of inflammatory bowel disease known to depend on an epithelial defect, and determine how such alterations contribute to the pathogenesis of inflammation and/or the generation of symptomatology. The interplay with luminal bacteria will also be sought. In the second aim, we will define mechanisms whereby probiotic microorganisms improve epithelial barrier and transport function under control conditions, when these functions are compromised in vitro, and in the model of inflammatory bowel disease described above. The approach will be to use the mdr1a -/- mouse which develops spontaneous colitis when conventionally housed, as well as human intestinal epithelial cell lines. We will also employ pathogenic bacteria and two representative probiotic strains. We will study transport and barrier functions in these models using electrophysiological approaches, and will apply molecular techniques to define protein targets of inflammation, or which underlie the beneficial effects of probiotics. The significance of this work lies in its potential to yield novel insights into the pathogenesis of inflammatory bowel disease. It may also provide a scientific rationale for continued exploration of probiotics, promising complementary/alternative therapies, in the treatment of inflammatory bowel disease and other intestinal disorders.

描述（由申请人提供）：我们的长期目标是了解肠上皮运输和屏障功能。大量证据表明，在炎症性肠病和其他肠道疾病的情况下，这些关键功能发生了改变。此外，我们假设当肠道屏障功能不足以排除腔内因子时，会导致炎症性肠病，从而导致免疫刺激以及炎症和损伤的恶性循环，从而进一步损害了运输和障碍的体内平衡。我们还将检验以下特定假设：益生菌微生物在两种基础条件下以及肠上皮细胞以及被致病性微生物或其他有害侮辱所损害时对肠上皮细胞产生保护作用。我们将通过解决两个具体目标来检验我们的假设。首先，我们将检查障碍物和运输功能是否在已知取决于上皮缺陷的炎症性肠病模型中是否发生了变化，并确定这种改变如何有助于炎症和/或症状产生的发病机理。还将寻求与腔细菌的相互作用。在第二个目的中，我们将定义机制，即益生菌微生物在对照条件下，当这些功能在体外以及上述炎症性肠病的模型中损害时，改善上皮屏障和运输功能。该方法将是使用MDR1A - / - 小鼠，该MDR1A - / - 小鼠在常规饲养时会出现自发性结肠炎以及人类肠上皮细胞系。我们还将采用致病性细菌和两种代表性的益生菌菌株。我们将使用电生理方法研究这些模型中的运输和屏障功能，并将应用分子技术来定义炎症的蛋白质靶标，或者是益生菌的有益作用的基础。这项工作的意义在于它的潜力有可能产生对炎症性肠病发病机理的新见解。它还可以为继续探索益生菌，有希望的补充/替代疗法，治疗炎症性肠病和其他肠道疾病的科学原理。