The gastrointestinal (GI) tract is responsible for digestion and nutrient absorption and it contributes to water balance and immune function. The GI tract begins its development during the prenatal period but as with other organs of the body, it continues to mature postnatally. Most basic research on GI development has focused on the prenatal period with little attention given to postnatal maturation. Closing this knowledge gap is important for understanding childhood gastrointestinal motility and visceral hypersenstivity disorders, which place a large burden on the affected children and their families. Studies in this exploratory proposal will test the hypothesis that 5-HT signaling from enterochromaffin (EC) cells is not fully developed at birth and that this important signaling system matures postnatally. We will also test the hypothesis that 5-HT release in the mucosal villi is a signal that stimulates SERT expression during the postnatal period. As the anatomy and physiology of the ENS have been best defined in guinea pigs, studies in this proposal will mainly use this animal model. Mice will also be used in some studies to take advantage of genetically modified animals to test our hypothesis. We will use wild type and tryptophan hydroxylase 1 (TpH1) gene knockout mice. TpH1 is the enzyme largely responsible for 5-HT synthesis in the gut. Our use of continuous amperometry to measure 5-HT release from EC cells in real time will enable quantitative assessments of the development of this important signaling system during postnatal development. Release measurements will be correlated with expression or function of TpH, the serotonin transporter (SERT) or serotonin receptors (5-HT2A and/or 5-HT2B). We will also use gastrointestinal epithelial cell lines to study 5-HT signaling and SERT expression at the cell and molecular biological level. These studies will lay the groundwork for more extensive mechanistic studies, in the future, of postnatal development of neurohumoral mechanisms controlling gastrointestinal function. It is anticipated that these studies will also provide new insights into potential pathophysiological changes that might be responsible for childhood gastrointestinal motility disturbances.
Current knowledge of the structure and function of enteric nerves is based on studies done in adult or embryonic animals. Little information is available on development of enteric nerves during the postnatal period. Our studies will focus on postnatal maturation of enteric signaling mechanisms in an effort to understand the causes of pediatric gastrointestinal motility disorders.
| Galligan, J J; Patel, B A; Schneider, S P et al. (2013) Visceral hypersensitivity in female but not in male serotonin transporter knockout rats. Neurogastroenterol Motil 25:e373-81 |
| Hoffman, Jill M; Tyler, Karl; MacEachern, Sarah J et al. (2012) Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 142:844-854.e4 |
| Zhao, H; Sovadinova, I; Swope, V M et al. (2011) Postnatal development of the serotonin signaling system in the mucosa of the guinea pig ileum. Neurogastroenterol Motil 23:161-8, e40 |
| Patel, B A; Dai, X; Burda, J E et al. (2010) Inhibitory neuromuscular transmission to ileal longitudinal muscle predominates in neonatal guinea pigs. Neurogastroenterol Motil 22:909-18, e236-7 |
