Our central hypothesis is that fibroblasts regulate the availability of IGF-I to gut epithelial cells through IGF binding proteins (IGFBP), thereby governing a crucial agent of mucosal development. To test this hypothesis, we will utilize two models of enterocyte migration as assays for IGF-I effect. The first model uses epithelial cell wound-healing assays (which we and others have demonstrated to be responsive to IGF-1 availability) that will be co-cultured with transgenic fibroblast containing integrated, tetracycline-regulated IGFBP-4 or -5. These experiments will determine how the selective production of IGFBP affects IGF-I availability. The second model is an in vivo model of dexamethasone-mediated maturation of the ileal mucosa in newborn mice. We will utilize a transgenic IGF-overexpressing strain to investigate the effect of gene dosage on epithelial cell migration rate, during both normal and dexamethasone-accelerated mucosal maturation. We will also use laser capture microscopy with Western blot assessment of the regional mucosal abundances of IGFBP-4 and IGFBP-5 during normal and accelerated maturation. The candidate is committed to a research career in academic medicine with a focus on development-related gut disease in the neonate. He first became interested in bowel development as a pediatric resident when, during a rash of late-night neonatal transports, he noticed a relationship between early postnatal dexamethasone and small bowel perforations in extremely premature infants. A burning desire to understand the developmental events associated with these perforations has led to an accelerated neonatology fellowship, four relevant 1st author publications, and an unwavering commitment to clinically relevant research. His long-term career goal is to utilize knowledge discovered in basic science to facilitate prevention and management of development-related bowel disease but also to contribute to the global understanding of gastrointestinal diseases that manifest aberrant tissue growth. The University of Virginia School of Medicine has a long track record in training independent basic investigators. The primary mentor, Dr. Victoria Camerini, has a productive record in both research and research training (she currently holds an RO1 and is a mentor for an NRSA grant). The candidate?s extended mentorship committee consists of individuals who each bring a unique skill or expertise to this proposal and the multiple research support centers (both at UVA and UNC) will provide opportunities for technical training.
Showing the most recent 10 out of 11 publications
