Barrier Function of the GI Tract in Health and Disease

总体描述（由申请人提供）： 本计划项目更新申请继续关注肠细胞在微生物和肠毒素介导的刺激与免疫效应器应答之间界面处的粘膜屏障功能中的作用。肠上皮细胞是中心焦点，将研究微生物的“串扰”免疫上皮细胞的相互作用，神经肽受体的表达，不适当的发育反应，和微生物渗透的障碍。该更新申请包括五个由两个核心支持的交互式项目，（1）和管理核心，以及（2）异种移植和同种移植移植模型核心，主要位于马萨诸塞州总医院东部的粘膜免疫学/发育胃肠病学实验室的一个位置。项目1将研究促肾上腺皮质激素释放激素家族的神经肽及其受体参与肠毒素和细菌病原体引起的粘膜炎症发展的机制。项目2将确定IkappaB在肠道中发育调节表达的机制基础，并评估IFN γ在发育中肠道免疫成熟中的作用。胎儿和成熟的肠上皮细胞在Toll样受体相关反应的发育差异也将进行检查。项目3将研究S.福氏肠上皮细胞在顶端或基底侧膜域的相互作用，导致急性感染性结肠炎。项目4将确定GEF-H1（Rho的鸟嘌呤核苷酸交换因子（GEF））在上皮细胞对病原体反应中的作用，并在紧密连接水平上研究这种反应的机制。项目5是一个新的项目，将定义益生菌制剂S的保护和治疗作用所涉及的特定细胞和分子机制。布拉氏菌在肠道感染和肠毒素介导的腹泻和肠道炎症。具有细胞/分子生物学，微生物学，肠道免疫和炎症以及发育生物学学科的研究人员将以合作的方式工作，以确定炎症和粘膜防御背景下的微生物肠毒素/上皮反应。这些研究将提供对细菌GI感染和肠毒素介导的肠道炎症的发病机制的更好理解，并导致预防和治疗GI道中的感染性疾病的新的治疗策略。

DESCRIPTION, OVERALL (provided by applicant): This Program Project renewal application continues to have a narrow focus on the role of the enterocytes in mucosal barrier function at the interface between microbial and enterotoxin-mediated stimuli and immune effector responses. The enterocyte is the central focus and will be studied with regard to microbial "crosstalk" immune-epithelial cell interactions, neuropeptide receptor expression, inappropriate developmental responses, and a barrier to microbial penetration. This renewal application consists of five interactive projects supported by two cores, (1) and Administrative Core, and (2) a Xenograft and Isograft Transplant Model Core, principally in one location in the Mucosa Immunology/Developmental Gastroenterology Laboratories at the Massachusetts General Hospital-East. Project 1 will examine the mechanisms involved in the participation of corticotropin-releasing hormone family of neuropeptides and their receptors in the development of mucosal inflammation in response to enterotoxins and bacterial pathogens. Project 2 will determine the mechanistic basis for the developmentally regulated expression of IkappaB in the intestine and evaluate the role of IFNgamma in immunologic maturation of the developing intestine. Developmental differences between fetal and mature enterocytes in Toll-like receptor-related responses will also be examined. Project 3 will study the molecular mechanisms underlying S. flexneri-intestinal epithelial interactions at the apical or basolateral membrane domain that lead to acute infectious colitis. Project 4 will determine the role of GEF-H1, a guanine nucleotide exchange factor (GEF) for Rho, on epithelial cell responses to pathogens and examine the mechanism of this response at the tight junctional level. Project 5 is a new project that will define specific cellular and molecular mechanisms involved in the protective and therapeutic effects of the probiotic agent S. boulardii in enteric infections and enterotoxin-mediated diarrhea and intestinal inflammation. Investigators with disciplines in cell/molecular biology, microbiology, intestinal immunity and inflammation, and developmental biology will work in a collaborative fashion to define microbial-enterotoxin/epithelial responses in the context of inflammation and mucosal defenses. These studies will provide a better understanding of the pathogenesis of bacterial Gl infections and enterotoxin mediated intestinal inflammation and lead to new therapeutic strategies in preventing and treating infectious diseases in the Gl tract.