Over the past decade, the treatment of IBD has not advanced past steroid and anti-biological agents targeted at inflammatory pathways. Due to the side-effects of these agents and the sometimes refractory nature of IBD, novel therapeutics that target the epithelial lining of the GIT to promote mucosal healing are becoming the gold standard for emerging treatments of IBD. The epithelium plays a key role in maintaining homeostasis of the gut through its function as a selectively permeable, physical barrier. When the epithelium is damaged, its protective function is compromised. In order to restore gut homeostasis, mucosal wound healing occurs to ensure the epithelial barrier is repaired. During chronic inflammation of the gut such as in seen in IBD, the mucosal tissue undergoes continuous cycles of mucosal damage and repair, with inefficient mucosal wound healing exacerbating the inflammatory state. The mucosal damage associated with IBD inflammation also creates a microenvironment with relatively low oxygen levels (hypoxia). However, the mechanisms underlying mucosal wound healing in the gut during inflammatory hypoxia remain poorly understood. Previous studies in our lab have identified the transcription factor, hypoxia inducible factor (HIF)-1, as a critical regulator in the coordinated process of mucosal wound healing. Our data suggests that HIF-1 mediates wound healing in the gut through the regulation of cell adhesion molecules, integrins. This project aims to address the fundamental concept that HIF-1 mediates mucosal wound healing through coordinated induction of integrins, and that this pathway may be utilised for the development of novel treatments for IBD. Using a multidisciplinary approach to evidence-based discovery, this research aims to drive the development of novel IBD therapeutics. This process is based upon the strategy of confirmation of hypotheses in vitro in cell lines, and in vivo validation using wellestablished murine models of colitis and wound healing.
Inflammatory bowel disease (IBD) is characterised by chronic, immune-mediated inflammation of the gastrointestinal tract (GIT) and encompasses a number of conditions including ulcerative colitis (UC) and Crohn’s disease (CD). Due to the seriously debilitating nature of IBD, novel therapeutics to improve IBD patient quality of life is a significant healthcare need.