Developmental Genetics of Gut and Pancreas in Zebrafish

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DESCRIPTION (provided by applicant) The candidate for this award is a pediatric gastroenterologist with a Ph.D. in molecular biology who plans to study the genetic basis of digestive organogenesis. He is pursuing training in developmental biology to this end. The career development plan will focus initially on acquiring basic knowledge and experimental skills. During subsequent years, activities will be geared to establishing an independent research program as part of the Developmental Gastroenterology Laboratory at MGH-East, a plan supported by Dr. W. Allan Walker, the director of that laboratory and the candidate's co-sponsor. The candidate's primary sponsor is Dr. Mark C. Fishman, an accomplished worker in zebrafish research. Dr. Fishman's laboratory has the funding, personnel, equipment and aquaculture facility necessary for the candidate to carrying out the proposed research and career development plans. The institutional environment is that of Massachusetts General Hospital and Harvard Medical School, which support a critical mass of researchers who collectively represent the leading edge of many different fields, including developmental biology. The proposed research will identify and characterize a genetic mutation in the zebrafish which exhibits abnormal intestinal cell polarity, agenesis of the exocrine pancreas, and a structural anomaly resembling imperforate anus, a common human birth defect. Specific aim 1 is to isolate the gene by positional cloning. Specific aim 2 is to determine the timing and location of gene expression at the RNA and protein levels. Specific aim 3 is to determine if the cell autonomy of gene function by chimeric embryo analysis. The results of these experiments may reveal fundamental mechanisms by which epithelial cells differentiate in the digestive tract, a phenomemon that is not well defined at the molecular level. In the future, the candidate hopes to extend this work into mammalian systems, and draw on his medical training to relate the work to understanding human digestive diseases, particularly those affecting children.