Barrier Function of the GI Tract in Health and Disease

胃肠道的屏障功能在健康和疾病中的作用

• 批准号: 8013264
• 负责人: W ALLAN WALKER
• 金额: $ 8.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013264
• 关键词: Acute; Apical; Cell Communication; Cells; Colitis; Communicable Diseases; Corticotropin-Releasing Hormone; Development; Developmental Biology; Diarrhea; Discipline; Disease; Enteral; Enterocytes; Enterotoxins; Epithelial; Epithelial Cells; Family; Gastroenterology; Gastrointestinal tract structure; General Hospitals; Guanine Nucleotide Exchange Factors; Health; I Kappa B-Alpha; Immune; Immunity; Immunologics; Infection; Inflammation; Inflammatory disease of the intestine; Intestines; Isogenic transplantation; Laboratories; Lead; Location; Massachusetts; Mediating; Microbiology; Modeling; Molecular; Molecular Biology; Mucositis; Mucous Membrane; Neuropeptide Receptor; Neuropeptides; Pathogenesis; Penetration; Probiotics; Research Personnel; Role; Shigella flexneri; Stimulus; Therapeutic Effect; Toll-like receptors; Transplantation; Work; Xenograft procedure; base; basolateral membrane; developmental immunology; fetal; microbial; novel therapeutics; pathogen; prevent; programs; receptor; receptor expression; response; rho

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.

描述，总体（由申请人提供）： 该计划项目更新应用程序继续关注肠细胞在微生物和肠毒素介导的刺激和免疫效应子反应之间的接口上的肠细胞在粘膜屏障功能中的作用。该肠环是中心焦点，将研究微生物“串扰”免疫上皮细胞相互作用，神经肽受体表达，不适当的发育反应以及微生物渗透的障碍。该更新应用程序由五个互动项目组成，该项目由两个核心（1）和行政核心支持，以及（2）一个异种移植和异流移植模型核心，主要位于马萨诸塞州粘膜免疫学/发育性胃肠道实验室的一个位置。项目1将研究神经肽释放皮质激素激素家族及其受体参与粘膜炎症的发育中涉及的机制，以响应肠毒素和细菌病原体。项目2将确定Ikappab在肠道中发育调节表达的机理基础，并评估Ifngamma在发育中的肠道免疫成熟中的作用。还将检查胎儿和成熟的肠细胞在类似受体相关的反应中的发育差异。项目3将研究顶端或基底外侧膜结构域的柔性链球菌上皮相互作用的分子机制，导致急性感染性结肠炎。项目4将确定RHO的GEF-H1（鸟嘌呤核苷酸交换因子（GEF））对病原体的上皮细胞反应的作用，并检查紧密连接水平的该反应的机制。项目5是一个新项目，它将定义益生菌链球菌在肠道感染和肠毒素介导的腹泻和肠炎中涉及的特定细胞和分子机制。在细胞/分子生物学，微生物学，肠道免疫和炎症以及发育生物学方面的研究人员将以协作的方式起作用，以在炎症和粘膜防御范围内定义微生物 - 肠内毒素/上皮反应。这些研究将更好地理解细菌GL感染和肠毒素介导的肠炎的发病机理，并导致预防和治疗GL区传染病的新治疗策略。