From Genes to Disease: Investigating the Role Of ECM1 Variants in the Pathogenesis of Inflammatory Bowel Disease. (360G-Wellcome-104503_Z_14_Z)

Inflammatory bowel disease affects 1:250 people in the UK. It is a chronic condition associated with significant morbidity. It comprises two principle forms; Crohns Disease and Ulcerative Colitis (UC). Genome wide association scanning has identified gene variants involved in maintenance of the intestinal epithelial barrier as being associated with UC including ECM1. In yeast models ECM1 binds and inhibits matrix metalloproteinase 9 (MMP9), a protease involved in tissue remodelling which has been implicated in colitis pathogenesis. I propose to investigate the function of ECM1 and its variants and to define the interaction between ECM1 and MMP9 within a disease appropriate model. The hypothesis is that ECM1 variants cause functional attenuation reducing the inhibitory effect on MMP9 leading to increased tissue breakdown and thereby a dysfunctional intestinal epithelial barrier. My research objectives are: 1. To determine the conditions under which ECM1 and MMP9 associate i n human colonic epithelial cells 2. To determine the requirement for ECM1 in maintaining epithelial cell barrier integrity. 3. To determine the impact of ECM1 variants on ECM1 function This may allow us to stratify patients susceptibility to IBD and highlight potential therapeutic targets.