BACTERIAL EPITHELIAL CROSSTALK IN DEVELOPING INTESTINE

这个实验室已经研究了二十年的肠道宿主防御的发展， 定植和入侵微生物、其毒素和外来抗原。我们已经证明 在许多情况下，未成熟的人肠上皮细胞不能抵抗病原体，或者对微生物/微生物毒素-肠上皮细胞“串扰”反应不适当。在最后的研究期间，我们已经表明，外毒素（霍乱毒素）和内毒素（脂多糖）的反应是过度的和不成熟的人肠上皮细胞不能区分肠道和病理定植细菌由于IkappaB的低表达的不成熟肠上皮细胞。基于这些先前的观察，我们假设不成熟的（不适当的）肠上皮细胞对定植细菌的反应可能是年龄相关的胃肠道感染性/炎症性疾病的原因。为了验证这一假设，我们将研究细菌上皮细胞的“串扰”在发展中的肠上皮细胞对细菌和其保守的病原体相关分子模式（PAMPs）的反应的分子特征。因此，我们的具体目标是通过使用未成熟与成熟的肠上皮细胞。A1.确定肠中IkappaB发育调控表达的机制基础。A2.评价IFN-γ在发育中的肠道免疫成熟和调节肠道炎症中的作用。A3.通过确定胚胎和成熟肠上皮细胞在TLR表达和对定植和炎症刺激后PAMPs反应方面的发育差异，研究TOII样受体（TLR）家族（特别是TLR 2、4、5）在此过程中的作用。这些研究的结果应该提供了一个更好的了解如何殖民细菌与发展中的肠道相互作用，并可能建立激活正常的微生物上皮“串扰”和预防年龄相关的新生儿胃肠道疾病的策略。

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.