(taken from application) The candidate: Dr. Furuta began working in a basic science laboratory during his GI fellowship. This experience led him to choose a career path that would allow him to become a basic scientist. He received a National Research Service Award and a Career Development Award from the Crohn's Colitis Foundation. He has demonstrated the sustained productivity necessary to become an independent investigator. He now seeks to develop skills in molecular gene regulation and epithelial physiology that will permit him to study the role of the eosinophil in GI disease. He is committed to a career in academic medicine and basic science research. The environment: The candidate will work under the close supervision of expert's in gene regulation, epithelial ion secretion, eosinophil biology and gastrointestinal immunology. Dr. Tenen will serve as the primary mentor and Drs. Colgan, Ackerman and Wershil as co-mentors. Dr. Furuta has worked with each of his mentors previously and has established solid working relationships. The Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, and Harvard Medical School are committed to providing nurturing scientific environments. These environments provided both the physical plant necessary to complete the proposed studies and the training activities necessary of his development into an independent investigator. His division is committed to providing the protected time and salary support to completed the studies detailed in this proposal. The research: A number of gastrointestinal disease are characterize by the infiltration of eosinophils into the tissue layers, but the precise participation of the eosinophil in GI disease has not been defined. In preliminary data, we show that eosinophil-derived major basic protein can 1. induce the production of IL-8 from intestinal fibroblasts, 2. potentiate chloride secretion from colonic monolayers, and 3. induce tissue swelling and neutrophil infiltration in a murine model of inflammation. These findings suggest new mechanisms by which eosinophils may participate in the in [sic] GI diseases. We hypothesize that eosinophil derived granule proteins (EDGPs) participate in GI disease by stimulating pro-inflammatory cytokine/chemokine production and epithelial chloride secretion. We will determine the mechanisms of: 1. EDGP stimulated IL-8 production in intestinal fibroblasts and EDGP stimulated neutrophil transmigration across intestinal epithelium, 2. EDGP stimulated epithelial cell chloride ion secretion and 3. EDGP stimulated neutrophil infiltration, changes in vascular permeability and fluid secretion in vivo.
