Barrier Function of the GI Tract in Health and Disease

描述(申请人提供)：本计划项目续签申请继续侧重于肠细胞在微生物和肠毒素介导的刺激和免疫效应反应之间的界面上的粘膜屏障功能中的作用。肠细胞是中心焦点，将从微生物的“串扰”和免疫-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等方面进行研究。续签申请包括五个互动项目，由两个核心支持，(1)行政和(2)异种移植/同种移植，人体肠道组织和成像核心主要在马萨诸塞州东部总医院(BIdg 114)粘膜免疫实验室的一个地点。项目1将研究NFkappaB/MyD88先天反应基因以及胎儿与成熟肠细胞中其他炎症途径的不成熟，以帮助解释早产儿过度的肠道炎症，并测试氢化可的松和益生菌的成熟预防。项目2将研究促肾上腺皮质激素释放激素家族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3将研究导致急性感染性结肠炎的福氏志贺氏菌与肠上皮细胞在顶端或基侧膜域相互作用的分子机制。项目4将确定全球环境基金-H1，一种鸟嘌呤核苷酸交换因子(Rho)，在上皮细胞对病原体的反应中的作用，并在紧密连接水平上研究这种反应的机制。项目5将确定在肠道感染和肠毒素介导的腹泻和肠道炎症中益生菌.S.Boulardii的保护和治疗效果所涉及的具体细胞和分子机制。拥有细胞/分子生物学、微生物学、肠道免疫学和炎症与发育生物学学科的研究人员将更好地了解细菌性Gl感染和肠毒素介导的肠道炎症的发病机制，并可能导致预防和治疗Gl区传染病的新的治疗策略。 公共卫生相关性：本计划项目研究定植细菌如何刺激肠道宿主防御，防止病原体及其毒素引起的炎症，作为翻译贡献。所做的观察可能导致预防肠道传染病的策略。 目录 总体描述2

DESCRIPTION (provided by applicant): This Program Project renewal application continues to have a narrow focus on the role of 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" and 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) An Administrative and (2) Xenograft/lsograft Transplant, human intestinal tissue and imaging core principally in one location in the Mucosal Immunology Laboratory at the Massachusetts General Hospital-East (BIdg 114). Project 1 will examine immaturities in NFkappaB/MyD88 innate response genes and in other inflammatory pathways in fetal vs. mature enterocytes to help explain excessive intestinal inflammation in prematures and test maturational prevention with hydrocortisone and probiotics. Project 2 will examine the mechanisms involved in the participation of corticotrophin releasing hormone family of neuropeptides and their receptors in the development of mucosal inflammation in response to enterotoxins and bacterial pathogens. 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 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 provide a better understanding of the pathogenesis of bacterial Gl infections and enterotoxin-mediated intestinal inflammation and may lead to new therapeutic strategies in preventing and treating infectious diseases in the Gl tract. PUBLIC HEALTH RELEVANCE: This Program Project examines how colonizing bacteria stimulate intestinal host defense and prevents inflammation by pathogens and their toxins as a translation contribution. Observations made may lead to strategies for prevention of intestinal infectious disease. TABLE OF CONTENTS Overall Description 2