The candidate is a pediatric surgeon with a strong background in developmental biology who plans to study the mechanisms underlying development of the enteric nervous system (ENS) and elucidate how it may explain disorders of intestinal motility in children. The career development plan focuses initially on acquiring basic knowledge and experimental skills, facilitated by participation in coursework and national meetings. The later years will be aimed at establishing an independent research effort within the Pediatric Surgical Laboratories at Massachusetts General Hospital, a goal strongly supported by Dr. Patricia Donahoe, director of that laboratory and chief of Pediatric Surgery. The candidate's co-sponsors, Dr. W. Allan Walker and Dr. Drucilla Roberts, accomplished investigators in the proposed field of study, have also committed their scientific expertise and resources to advancing the goals of this application. The institutional environment at Massachusetts General Hospital and Harvard Medical School provides an outstanding opportunity to successfully pursue this Mentored Clinical Scientist Development Award. ? ? The proposed research focuses on the ENS, a complex neuronal network essential for maintaining a functional gastrointestinal tract. The ENS is comprised of neurons arising primarily from vagal neural crest cells that populate the bowel in a craniocaudal wave of migration. Hirschsprung's disease, a common and severe cause of bowel obstruction in children, resulted from abnormal neuronal migration, leaving the distal bowel aganglionic. Preliminary evidence in chick embryos demonstrates that hindgut-targeted viral misexpression of Bapx1 or noggin inhibits expression of the signaling molecule BMP4 and leads to intestinal aganglionosis, implicating an essential role for BMP signaling in ENS development. This application first aims to fully characterize this novel model of Hirschsprung's disease and establish the role of BMP signaling in ENS development. Organ culture experiments using isolated vagal neural crest and hindgut from wild-type and injected embryos will further define the roles of these genes in ENS development. Finally, human tissue from patients with Hirschsprung's disease and other congenital motility disorders will be examined by in situ hybridization to assess the importance of BMP signaling in the clinical arena, thereby enhancing the understanding of these disorders and helping to refine the diagnosis and treatment of these disabling conditions in children. ? ?
