Targeting Nuclear Receptors to Treat Fibrostenotic Crohn's Disease

Abstract

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 ileitis(SAMP/YitFcsJ 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.

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Document Details

Document Type
Technical Report
Publication Date
Oct 01, 2018
Accession Number
AD1096408

Entities

People

  • Simon A Hirota

Organizations

  • University of Calgary

Tags

DTIC Thesaurus Topics

  • Acquisition
  • Body Weight
  • Cells
  • Diseases And Disorders
  • Fibroblasts
  • Fibrosis
  • Health Care
  • Health Services
  • Inflammation
  • Intestinal Diseases
  • Medical Personnel
  • Muscle Cells
  • Muscles
  • Pathologic Constriction
  • Smooth Muscle
  • Targeting
  • Tissues

Fields of Study

  • Biology
  • Medicine

Readers

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  • Molecular and Cellular Biology