Scientific Abstract

Proposal No. IBD-0212
Principal Investigator:  John H. Kwon, M.D., Ph.D.
Applicant Organization:  Johns Hopkins University (Baltimore, Maryland, U.S.A.)
Project Title:  The differential expression of microRNA in ulcerative colitis patients and their regulation of MIP-2α expression
Period of Award:  July 1, 2007 – January 31, 2010

Multiple global gene expression profiles demonstrate that IBD is associated with increased mRNA expression of genes involved in inflammation and fibrosis. The mechanisms by which these genes are persistently increased in IBD are not fully understood. MicroRNAs (miRNAs), a group of small (~22 nucleotide) non-coding RNAs encoded in the human genome, which influence gene expression by acting as potent regulators of mRNA degradation and translational inhibition. miRNAs are differentially expressed in developing tissues, numerous cancers and some human diseases. They have been implicated in cellular processes of differentiation, proliferation and apoptosis. Recently, miRNAs were implicated as negative regulators of inflammation and innate immunity. However, their expression and role in chronic inflammatory diseases such as IBD have not been examined.

We hypothesize that the sustained, increased expression of genes involved in inflammation and fibrosis in IBD may be due to a down-regulation of miRNA species that normally suppress expression of these genes. Our preliminary results demonstrate that miRNAs are differentially expressed in tissues of patients with active UC compared to normal, healthy controls. These preliminary data also indicate that miRNAs can regulate colonic epithelial cell expression of the chemotactic cytokine, macrophage inflammatory peptide (MIP)-2α. In the current proposal, we will investigate the tissue expression and cellular localization of miRNAs in patients with active UC compared to inactive UC, other inflammatory bowel diseases and normal healthy control subjects. We will also further our understanding of the role of miRNAs in the regulation of MIP-2α expression as well as other miRNA targets. Results of these investigations will greatly increase our understanding of the mechanisms controlling inflammation. Ultimately, these results may lead to the development of miRNA-based therapeutic agents for IBD.