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Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain associated with alteration in stool form and/or frequency. The pathophysiology of IBS is poorly understood. Although structural or histological changes in the gastrointestinal tract are absent in IBS, changes in intestinal function (e.g. increased intestinal permeability, increased neuronal sensitivity) and changes at the molecular level (e.g. gene methylation, gene/protein expression) have been described.This dissertation describes a translational research project which began with data from gastrointestinal biopsies and concluded with studies in cell culture models. We performed a microarray gene expression profiling analysis of colonic mucosal biopsies in patients with IBS and healthy controls. I analyzed the differential gene and described the pathways involved in the regulation of IBS. These studies have direct clinical impact to patient care. Since data in the literature suggests a role for epigenetic changes (changes affecting gene expression) in IBS, I next focused on the role of differentially expressed long non-coding RNAs in IBS. The long non-coding RNA afadin-divergent transcript (AFDN-DT), which was up-regulated in IBS, was selected for further in vitro studies. I generated intestinal epithelial cell lines capable of inducible expression of AFDN-DT and tested the hypothesis that overexpression of AFDN-DT resulted in altered epithelial permeability. |
