Coordinated communication between the enteric nervous system (ENS) and other tissue types is necessary for regular function and motility of the intestine. Gastrointestinal (GI) motility disorders are a substantial clinical burden with more than 25% of pediatric GI referrals arising from chronic constipation and 63 million people in the US alone suffering from chronic constipation. Hirschsprung disease (HSCR) is an example of a severe, congenital GI motility disorder that affects approximately 1 in 5000 people and occurs due to aberrant development of the enteric nervous system. Mild cases manifest as constipation while severe cases lead to toxic megacolon and death. HSCR is defined by aganglionosis of the distal gastrointestinal tract and is in part due to the abnormal migration of neural crest (NC) derived progenitors of the enteric nervous system. The first line of treatment for pediatric HSCR patients is surgical resection of the aganglionic portion of their bowel. However, many patients continue to suffer from intestinal dysfunction, including motility disorders and enterocolitis, despite the presence of ganglia in the intact proximal bowel. The basis for these chronic symptoms is unknown and suggests that abnormal neural crest migration is not the only factor contributing to the HSCR phenotype. We hypothesize that aberrant lineage segregation and differentiation of neural progenitors in proximal regions of the intestine contributes to the continuing gut dysmotility and related complications suffered by HSCR patients despite the presence of ganglia in intact proximal intestine. Abnormalities of lineage segregation occur among neural progenitors cultured in vitro from the Sox10Dom HSCR mouse model, but the effects of these imbalances in vivo on postnatal enteric ganglia in ganglionic regions of the HSCR intestine are not known. The proposed studies will investigate whether proximal enteric ganglia are defective in patterning, composition, and gross function in postnatal HSCR mouse models.
In Aim 1, Cre-LoxP fate mapping approaches will be used to examine lineage segregation patterns in the postnatal intestine of the Sox10Dom HSCR mousemodel.
Aim 2 will assess small intestinal motility and inflammation among three HSCR mouse models that represent the genes most commonly altered among HSCR patients: RetC620R, Ednrbtm1Ywa, and Sox10Dom.
Aim 3 will examine HSCR patient pathology specimens to determine if defects in enteric ganglia patterning and composition occur proximal to regions of aganglionosis. Determining the frequency of patterning and composition deficits in HSCR enteric ganglia above the aganglionic zone in HSCR mouse models and HSCR pediatric surgical resections will influence HSCR patient care and lead to a greater understanding of pathologies that underlie GI motility disorders.

Public Health Relevance

Normal development of the enteric nervous system is important as defects in development can affect gastrointestinal function and motility and lead to digestive diseases and disorders. This study aims to provide fundamental knowledge regarding neural crest development by elucidating how Hirschsprung gene mutations affect enteric nervous system development and gastrointestinal function. Findings from this research are likely to explain Hirschsprung patient postoperative outcomes, such as chronic constipation and inflammation, and significantly impact Hirschsprung patient care.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DK096831-02
Application #
8506996
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (M1))
Program Officer
Podskalny, Judith M,
Project Start
2012-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$47,232
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212