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.
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