As a pediatric surgeon, I have an intense interest in the management of intestinal failure in infants. The most common etiology of """"""""short-gut"""""""" in infants is from necrotizing enterocolitis, but may also arise from volvulus, atresias, gastroschesis, and Hirschsprung's disease. Following massive intestinal loss, the remaining intestine attempts to adapt by enhancing proliferation of intestinal stem cells and their progeny resulting in marked increases in the remaining mucosal surface area aiding absorption and digestion. Failure of this process to adequately compensate require many children to depend on parenteral nutrition (TPN) to sustain adequate nutrition subjecting them to the many inherent risks of TPN, including cholestasis and liver failure. Developing new therapies to augment the adaptive response will require an understanding of the mechanisms that stimulate intestinal stem cells and their progeny following massive intestinal loss. My ongoing studies in the laboratory of Susan Henning Ph.D. are evaluating the role of secretory lineages during intestinal adapation, and have demonstrated an early increased production of intestinal secretory lineages occurs following resection. I hypothesize that the early increased production of intestinal secretory lineages following massive intestinal loss is essential to amplify the early signals initiating intestinal adaptation. This grant proposes the use of a specific progenitor assay somatic mutation (SPASM) sytem to identify dynamic changes within intestinal progenitor compartments that occur following a 50% intestinal resection in mice. The early role of secretory lineages initiating intestinal adaptation will further be evaluated by performing similar intestinal resections on mice harboring a mosiac inactivation of all secretory lineages in the terminal ileum and on normal mice following administration of growth factors that previously have been shown to stimulate only secretory or columnar lineages. The development of flow cytometry techniques to separate and quantitate epithelial lineages will provide an efficient tool to further assess the molecular mechanisms initiating the early adaptive response. The excellent environment provided by Dr. Henning's laboratory and the support of this application will provide a solid foundation for the development of an independent translational reseach career exploring the mechanisms of intestinal adaptation and treatment of intestinal failure in children.
| Garrison, Aaron P; Dekaney, Christopher M; von Allmen, Douglas C et al. (2009) Early but not late administration of glucagon-like peptide-2 following ileo-cecal resection augments putative intestinal stem cell expansion. Am J Physiol Gastrointest Liver Physiol 296:G643-50 |
| Rigby, R J; Hunt, M R; Scull, B P et al. (2009) A new animal model of postsurgical bowel inflammation and fibrosis: the effect of commensal microflora. Gut 58:1104-12 |
| Garrison, Aaron P; Helmrath, Michael A; Dekaney, Christopher M (2009) Intestinal stem cells. J Pediatr Gastroenterol Nutr 49:2-7 |
| Helmrath, Michael A; Fong, Jerry J; Dekaney, Christopher M et al. (2007) Rapid expansion of intestinal secretory lineages following a massive small bowel resection in mice. Am J Physiol Gastrointest Liver Physiol 292:G215-22 |
| Dekaney, Christopher M; Fong, Jerry J; Rigby, Rachael J et al. (2007) Expansion of intestinal stem cells associated with long-term adaptation following ileocecal resection in mice. Am J Physiol Gastrointest Liver Physiol 293:G1013-22 |
| Shroyer, Noah F; Helmrath, Michael A; Wang, Vincent Y-C et al. (2007) Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 132:2478-88 |
