Regulation of Inflammation in Immature Intestine

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DESCRIPTION (provided by applicant): The Candidate: Dr. Claud began her research during her neonatology fellowship. Under the mentorship of Dr. Michael S. Caplan, she investigated the effect of platelet activating factor on ion transport. After her fellowship she joined the division of Newborn Medicine at The Children's Hospital (TCH), Boston and the Massachusetts General Hospital (MGH) laboratory of Dr. W. Allan Walker. She seeks to develop expertise in signal transduction in order to study the development of intestinal inflammatory regulation as it relates to the pathogenesis of necrotizing enterocolitis (NEC). She is committed to a career as a physician-scientist. The Environment: The candidate will work under the close supervision of experts in signal transduction, gastrointestinal immunology, and cell biology. Dr. Walker and Dr. Bobby Cherayil will serve as mentors. TCH MGH and Harvard Medical School are committed to providing a nurturing scientific environment. This includes laboratory space, access to senior scientists, and the training necessary for her development into an independent investigator. The neonatology division is committed to providing protected research time. The Research: Evidence suggests that intestinal epithelial-microbial interactions are developmentally regulated. Preliminary data demonstrate that compared to adult intestinal epithelial cells (IEC), human fetal IEC have an exaggerated production of interleukin 8 (IL-8) in response to exogenous (gram-negative bacteria, flagellin) and endogenous (tumor necrosis factor alpha, interleukin 1 beta) inflammatory mediators. The objective of this project is to delineate the mechanisms by which intestinal inflammation is regulated in the immature intestine at the cellular and molecular level. The hypothesis for this application is that altered receptor expression and/or signal transduction pathways in immature intestinal epithelium lead to an exaggerated inflammatory response to microbial and inflammatory mediator interaction. This application is designed to 1. Elucidate the mechanism behind increased stimulated IL-8 secretion in the immature intestine, and 2. Test the in vivo relevance of these findings. The experimental design utilizes cell and organ culture models, a rat model of NEC, and human NEC intestinal samples. These studies should begin to answer the critical question- "What is responsible for the initiation and perpetuation of the inflammatory state in NEC?"