Understanding sex-linked disease mechanisms in Hirschsprung's disease (360G-Wellcome-102491_Z_13_Z)

Hirschsprung's disease (HSCR) is a congenital disorder causing obstruction of the large intestine as partial or total innervation of the gut fails to occur in development. It is one of the most common causes of neonatal intestinal obstruction with incidence rates of up to 1.4/5000 live-births in China and 1/5000 in Caucasians. The most common form of the disease, short segment HSCR (S-HSCR), comprises 80% of HSCR cases and exhibits a strong sex bias with a 5:1 male to female ratio (Badner et al., 1990; Amiel et al., 2008; Garcia-Barcelo et al., 2009). This project aims to answer the disparity in HSCR incidence between males and females, and provides a tractable model to begin to investigate and understand sex bias in numerous diseases. We will focus on a number of mouse models with S-HSCR-like phenotypes for malebias and carry out genetic crosses utilising the "four core-genotype model" (De Vries et al., 2002). The two models showing the most robust sex bias will be chosen for further study. We will then investigate whether sex bias is sex chromosome-specific or gonad/hormone-specific, identifying HSCR-associated variants, genes and/or pathways that are significant in one gender and exploring differences in their activity and function.