Targeting Nuclear Receptors to Treat Fibrostenotic Crohn's Disease
Technical Report,01 Aug 2016,30 Jun 2018
THE UNIVERSITY OF CALGARY Alberta Canada
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While current therapies are effective in many patients with Crohns disease CD, others exhibit complications that require surgery. Fibrosis and increased smooth muscle SM thickening contributing to stricture formation and intestinal obstruction, occurs in 30-50 of CD patients within 10 years of disease onset. NR4A1 is an orphan nuclear receptor that has recently been identified as a key regulator of fibrosis and cell growth in non-intestinal systems. We found that NR4A1 activation reduces fibrosis and SM thickening, caused by established chronic inflammation, in a spontaneous CD-like model of ileitisSAMPYitFcsJ mouse. Deletion of Nr4a1 enhances fibrosis and SM thickening in the chronic DSS-model of colitis. In vitro, exposing primary intestinal fibroblasts IF to TGF-1 enhances the expression of NR4A1, whereas, NR4A1 activation suppressed TGF-1-induced expression of fibrotic genes, supporting the existence of an NR4A1-TGF-1 negative feedback loop.
- Medicine and Medical Research