FUNCTIONAL ANALYSIS OF INTEGRATED WNT SIGNALS FOR SELF-RENEWAL OF THE HUMAN COLONIC EPITHELIUM

The lining of the colon is formed by millions of invaginations called crypts. The majority of cells lining the colon are renewed every 5 days or so. Stem cells continuously produce immature cell offspring at the base of each crypt, which migrate upwards. After a few days the cells reach the crypt surface and undergo cell death. To sustain the normal function of the colon lining, the rate of cell death needs to be balanced by the rate of cell production. The mechanisms that coordinate cell production and cell death in the crypt are unknown. Wnt signals have recently been demonstrated to be a dominant force in the maintenance of the epithelium. However, the identity of the Wnt factors, specific signals and cellular processes are unknown. This study will utilise a novel combination of an intact model of the colon epithelium, state-of-the-art bioimaging techniques and molecular biology that are necessary to study the cellular signals activated by each Wnt factor and determine the consequences to the constant renewal of the colonic epithelium.

Wnt signalling pathways are emerging as master controllers of tissue renewal of skin, bone marrow and intestine. Wnt stimulation is regulated by the complex expression of secreted ligands, secreted antagonists, membrane receptor expression and downstream intracellular signalling components. Recent analysis of Wnt component expression suggests that integrated canonical and non-canonical Wnt signals regulate the self-renewal of the intestinal epithelium. Bioimaging and functional genomic approaches will be applied to a novel three dimensional model of the human colonic epithelium to study the mechanisms and role of Wnt signals in tissue renewal.