The onset of inflammatory bowel diseases (IBD), which includes Crohn's disease (CD) and ulcerative colitis, is poorly understood, but appears to involve a combination of host susceptibility, environmental factors and aberrant response to the luminal microbiota of the gut. One of the hallmarks of IBD is the upregulation of the pro-inflammatory cytokine TNF in various cell types, including immune and intestinal epithelial cells (IECs) and anti- TNF interventions are used as IBD therapy. In spite of its clinical relevance, little is known about the in vivo factors controlling TNF expression. In a forward zebrafish genetic screen we found that loss of the epigenetic regulators Uhrf1 or Dnmt1 leads to de-repression of the tnfa locus in IECs and microbe-dependent intestinal inflammation that resembles human CD. Our proposed research addresses the central hypothesis that defects in epigenetic regulation can trigger IBD onset in via de-repression of TNF. We will use the zebrafish system to define transcriptional and post-transcriptional mechanisms regulating tnfa expression and function in the intestine and how these are influenced by microbiota. We will also investigate whether CD patients carry mutations in DNMT1 or UHRF1 that may lead to loss of promoter methylation and de-repression of the TNF locus. These studies are expected to yield new mechanistic insights into IBD onset and may facilitate new approaches for IBD diagnosis and therapy.

Public Health Relevance

The onset of inflammatory bowel diseases (IBD), which includes Crohn's disease and ulcerative colitis, is poorly understood, but appears to involve a combination of host susceptibility, environmental factors and aberrant response to the luminal microbiota of the gut. The Crohn's and Colitis Foundation of America (CCFA) estimates that more than one million Americans are affected by IBD. Both diseases often require expensive and/or invasive measures for treatment, impair quality of life and predispose patients to an increased risk for colorectal cancer. These studies will bring new insights into IBD onset and may facilitate IBD diagnosis and new therapeutic approaches

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK113123-03
Application #
9900787
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2018-04-02
Project End
2022-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705