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: 6830684
• 负责人: Kim Elaine Barrett
• 金额: $ 26.75万
• 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/6830684
• 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(由申请者提供)：我们的长期目标是了解肠道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背景下，这些关键功能发生了变化。此外，我们假设炎症性肠病是当肠道屏障功能不足以排除管腔因素时导致的，从而导致免疫刺激和炎症和损伤的恶性循环，进一步损害运输和屏障动态平衡。我们还将测试这一特定假设，即益生菌在两种基本条件下以及当它们受到病原微生物或其他破坏性侮辱时对肠上皮细胞起保护作用。我们将通过解决两个具体目标来测试我们的假设。首先，我们将检查屏障和转运功能是否在已知依赖于上皮缺陷的炎症性肠病小鼠模型中发生改变，并确定这种改变如何有助于炎症的发病机制和/或症状的产生。还将寻求与腔细菌的相互作用。在第二个目标中，我们将确定益生菌在控制条件下改善上皮屏障和运输功能的机制，当这些功能在体外受到损害时，以及在上述炎症性肠病模型中。该方法将使用在常规饲养条件下发生自发性结肠炎的mdr1a-/-小鼠，以及人类肠道上皮细胞系。我们还将使用病原菌和两个有代表性的益生菌菌株。我们将使用电生理学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确定炎症的蛋白质靶点，或者是益生菌的有益效果的基础。这项工作的意义在于它有可能对炎症性肠病的发病机制产生新的见解。它还可能为继续探索益生菌在治疗炎症性肠病和其他肠道疾病中的补充/替代疗法提供科学依据。