An Antifibrotic Prodrug for the Prevention of Intestinal Scarring in Inflammatory Bowel Disease.

In Inflammatory Bowel Disease (IBD), inflammation of the digestive tract lining results in the development of chronic ulcers appearing throughout the intestines, colon or rectum. Although symptoms of IBD can be managed through the use of corticosteroids, complete disease remission is rare, often leading to surgical intervention. High expression of the transcription factor HIF-1_ is a key feature of regeneration in the Murphy Roths Large mouse, an inbred laboratory strain displaying remarkable regenerative capabilities. Recently, our team demonstrated enhanced regeneration of acute and chronic tissue wounds in adult mice following transient therapeutic upregulation of HIF-1_ using the experimental drug DPCA. Previous studies of HIF-1_ in IBD have been limited to preventative therapy and have not explored fibrosis inhibition or regeneration. Therefore, we hypothesize that transient upregulation of HIF-1_ can inhibit fibrosis of IBD lesions. We propose to study the effects of DPCA on 1) fibrosis in a human intestinal organoid (HIO) model; and 2) lesion development in a murine TGFb-induced model of intestinal fibrosis. This project will contribute to the development of a new clinical treatment for IBD, as an alternative or adjunct to existing therapies that focus on resolving inflammation, but do not address fibrosis.