BACTERIAL EPITHELIAL CROSSTALK IN DEVELOPING INTESTINE

肠道发育中的细菌上皮细胞串扰

• 批准号: 7487450
• 负责人: W ALLAN WALKER
• 金额: $ 17.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487450
• 关键词: Accounting; Adrenal Cortex Hormones; Animal Model; Antigens; Bacteria; Bacterial Infections; Cell Line; Cell model; Child; Cholera Toxin; Chronic; Complement 3a; Development; Disease; Endotoxins; Enterocytes; Epithelial; Epithelial Cells; Exotoxins; Exposure to; Family; Gastrointestinal Diseases; Gene Expression; Germ-Free; Host Defense; Human; I Kappa B-Alpha; IL8 gene; Immunologics; Inflammatory; Inflammatory disease of the intestine; Interferon Type II; Intestines; Invaded; Laboratories; Lipopolysaccharides; Localized; Modeling; Molecular; Mus; Neonatal; Organ Culture Techniques; Organism; Pathologic; Pattern; Probiotics; Process; Pus; Reaction; Regulation; Reporting; Research; Research Personnel; Role; Severities; Signal Transduction; Source; Stimulus; TLR2 gene; Testing; Toll-like receptors; Toxin; Transplantation; Weaning; Xenograft procedure; age related; base; commensal microbes; fetal; gastrointestinal; infancy; lipoteichoic acid; microbial; microorganism; pathogen; prevent; programs; receptor; receptor expression; response

This laboratory has for two decades studied the development of intestinal host defense against colonizing and invading microorganisms, their toxins and foreign antigens. We have shown that the immature human enterocyte in many instances fails to protect against pathogens or responds inappropriately to microbial/microbial toxin-enterocyte "crosstalk". During the last research period, we have shown that both the exotoxin (cholera toxin) and endotoxin (lipopolysaccharide) responses are excessive and immature human enterocytes fail to distinguish between commensal and pathologic colonizing bacteria due to an underexpression of IkappaB by immature enterocytes. Based on these previous observations, we hypothesize that an immature (inappropriate) enterocyte response to colonizing bacteria may account for age-related gastrointestinal infectious/inflammatory diseases. To test this hypothesis, we will study bacterial-epithelial "crosstalk" in the developing intestine with regard to the molecular characterization of the epithelial response to bacteria and their conserved pathogen-associated molecule pattern (PAMPs). Accordingly, our specific aims are by using immature vs. mature intestinal epithelial cells. A1. To determine the mechanistic basis for the developmentally-regulated expression of IkappaB in the intestine. A2. To evaluate the role of IFN-gamma in immunologic maturation of the developing intestine and in regulating intestinal inflammation. A3. To study of the role of the TOII-like receptor (TLR) family (particularly TLR2, 4, 5) in this process by determining developmental differences between fetal and mature enterocytes in TLR expression and response to PAMPs after colonization and inflammatory stimulation. The results of these studies should provide a better understanding of how colonizing bacteria interact with the developing gut and may establish strategies for activating normal microbial epithelial "crosstalk" and preventing age-related neonatal gastrointestinal disease.

该实验室已经二十年来研究了肠道宿主防御的发展 殖民和入侵微生物，其毒素和外抗原。我们已经表明 在许多情况下，未成熟的人类肠细胞无法预防病原体或对微生物/微生物毒素 - 肠细胞“串扰”的反应不当。在上一个研究期间，我们已经表明，外毒素（霍乱毒素）和内毒素（脂多糖）的反应都过度且未成熟的人类肠细胞无法区分由于iKappab的ikappression iKappab所导致的，均无法区分iKappab，而无效的肠肠球菌因iKappab而引起的病理性殖民细菌。基于这些先前的观察，我们假设对定植细菌的不成熟（不合适的）肠肠细胞反应可能是与年龄相关的胃肠道传染性/炎症性疾病的原因。为了检验这一假设，我们将研究发育中的肠道上的细菌 - 上皮“串扰”，这些关于上皮反应对细菌的分子表征及其保守的病原体相关分子模式（PAMPS）。因此，我们的具体目的是使用未成熟的肠上皮细胞。 A1。确定Ikappab在肠中发育调节表达的机械基础。 A2。评估IFN-GAMMA在发育中的肠道和调节肠道炎症中的免疫成熟中的作用。 A3。通过确定胎儿和成熟的肠细胞之间在TLR表达中的发育差异以及在定植和炎症刺激后对PAMP的反应，研究了TOII样受体（尤其是TLR2、4、5）的作用（尤其是TLR2、4、5）。这些研究的结果应更好地了解定殖细菌如何与发育中的肠道相互作用，并可能建立激活正常微生物上皮“串扰”并预防与年龄相关的新生儿胃肠道疾病的策略。