PhD North Carolina State University, Comparative Biomedical Sciences, 2014
Dissertation: Regulation of the Intestinal Barrier in Digestive Disease
DVM Jeju National University, Veterinary Medicine, 2009
Thesis: Effects of Lentinus edodes Extract on Loperamide-induced Constipation in Rats
My long-term research objective is to elucidate critical mechanisms by which the apical junctional complex contributes to intestinal epithelial homeostasis and pathogenesis of gastrointestinal disease. The apical junction complex, which includes tight junctions and adherens junctions, is required to regulate intestinal epithelial barrier function and intestinal homeostasis, and becomes dysregulated in important gastrointestinal pathological conditions including ischemic injury, inflammatory bowel disease, and colorectal cancer.
Role of chloride channel ClC-2 in Inflammatory Bowel Disease.
Treatment of patients with inflammatory bowel diseases (IBD) has been challenging, due to disease heterogeneity, and the lack of well-defined therapeutic targets. The intestinal barrier is comprised of epithelial cells linked by apical junctional complexes (AJCs), which are formed by tight junctions (TJs) and adherens junctions (AJs).In previous studies, the chloride channel, ClC-2, has been localized to the AJC regions in the intestine, and found that it contributes to regulation of intestinal barrier function, during the pathogenesis of IBD. However, it remains unclear how ClC-2 dysregulates the AJC, in intestinal dysfunction, during IBD pathogenesis. I have recently shown that ClC-2 is critical for the regulation of AJs, in colonic tissues. In those studies, the AJ proteins E-cadherin and β-catenin were markedly internalized, impeding colonic crypt differentiation in normal (non-colitis) ClC-2 knockout mouse colonic tissues and colonoids (‘mini-guts’), without concurrent alteration of TJ proteins, compared to wild type mice. Therefore, I propose that there is a critical need to determine the underlying mechanisms of ClC-2-associated AJ dysregulation, in IBD pathogenesis, using novel translational models such as CRISPR/Cas-induced ClC-2 knockout pigs, and human self-renewing monolayers, from colonic biopsies. My central hypothesis is that during IBD pathogenesis, the absence of ClC-2 markedly disrupts intestinal epithelial integrity, via dysregulation of AJ proteins, as compared to wild type controls.
Identify the Mechanism of Action of Larazotide Acetate.
Larazotide acetate (LA) is a synthetic, eight amino acid peptide that is known to act as a tight junction regulator capable of closing ‘leaky’ interepithelial junctions. Presently, LA is being studied in Phase 3 clinical trials for treatment of celiac disease. However, the mechanism by which LA regulates intestinal barrier is not fully understood. Therefore, we studied the mechanism of action of LA in several different digestive disease models including anoxic injury of Caco-2BBe1 cells and murine IBD models. The cellular pathways regulated by LA were studied using RNAseq, WB, IF, qPCR and etc.