The Role of the Enteric Nervous System in Necrotizing Enterocolitis

? DESCRIPTION (provided by applicant): I am an Assistant Professor in the Department of Surgery, Division of Pediatric Surgery, at the University of Minnesota. Although I manage a broad spectrum of pediatric disorders as a pediatric surgeon, I have developed a primary focus of interest in the role of the enteric nervous system (ENS) in intestinal inflammation and disease. My doctoral thesis during my combined medical training characterized the role of sphingolipid signaling in enteric glia, with particular emphasis on sphingosine-1-phosphate (S1P). My long- term career goal is to become an established independent investigator and to develop improved treatment options for children with debilitating intestinal diseases such as necrotizing enterocolitis (NEC). Environment: My primary mentor, Dr. Sabita Roy, and I work together in an enthusiastic and highly productive academic environment in conjunction with my other advisory committee members across the university. Our interdisciplinary approach involves state-of-the-art resources within the medical school and veterinary schools and beyond to allow us to unravel some the mysteries of the role of the ENS in intestinal inflammation and disease. Research: Necrotizing enterocolitis is a devastating and rising dilemma for premature infants. Recent evidence suggests that enteric glia may serve as gatekeepers in the intestine where they may help modulate inflammatory disorders in adults and children alike. This proposal seeks to gain further insight into sphingolipid signaling enteric glia in the context of NEC. Our studies demonstrate that enteric glia bear receptors for S1P and these receptors couple to downstream cellular events which may prove integral to the maintenance of gut barrier integrity in children with a developmentally mature enteric nervous system. Aim 1: Demonstrate enteric glial cell signaling contributes to normal gut barrier function in children. Aim 2: Establih that enteric glial signaling is undeveloped in children with necrotizing enterocolitis, contributin to disrupted gut barrier function. Summary: This K08 proposal serves as logical progression from my previous research experience in signaling events of glial cells the enteric nervous system, integrating the development of other essential skills though the guidance of my advisors. This application is designed to facilitate progression as a mentored scientist to that of an independent surgeon scientist with the chief aim of further characterizing the role of bioactive lipid signaling in glial cells of the enteric nervous system in childhood intestinal disorders of inflammation such as necrotizing enterocolitis.