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.

本实验室二十年来一直在研究肠道宿主防御的发展