Grant: Operating Grant

Hirschsprung disease (aganglionic megacolon) is a common birth defect of the gastrointestinal system, affecting 1 in 5000 newborn infants. Clinical signs include severe constipation and distended bowel due to a non-motile colon. Untreated, aganglionic megacolon is lethal. Developmentally, there is a failure of peripheral nerve cells to colonize the intestinal system during early gestation, resulting in a lack of enteric neural ganglia and thus defective neuromuscular function and normal peristalsis (motility). Aganglionic megacolon is a complex genetic disease that can involve mutations in multiple genes as well as environmental factors. It is estimated that mutations in known genes account for less than half of the cases of megacolon observed clinically. Therefore, further research must be conducted to improve diagnosis, treatment and genetic counseling. To this end, we have developed a novel mouse model for aganglionic megacolon which we have named TashT. TashT animals develop megacolon by two weeks after birth and succumb by three weeks. We have generated these mice via a random mutation approach and have identified the mutation site in a region of Chromosome 10 that has not been previously associated with Hirschsprung disease. We propose studies to determine which gene of this region is affected by the TashT mutation and which cellular mechanisms are disrupted in the TashT megacolon mice. We will also determine if the gene affected by the TashT mutation interacts with other known megacolon-associated genes as well as with environmental insults such as stress. Altogether, these studies will significantly further our understanding of the genetics and pathophysiology of this extremely severe enteric neuromuscular disorder.