The role of claudin-2 and its regulation in the development of intestinal inflammation.

摘要

The epithelium is a specialized tissue type that lines cavities and surfaces of organs and creates a barrier from the external environment. A strong barrier is established by the tight packing of epithelial cells and the tight junction, which creates a seal between cells. A large family of claudin proteins, that vary in small molecule selectivity, defines the barrier properties of the tight junction. Barrier dysfunction is present in various intestinal disorders and is characterized by increased flux of molecules across the epithelial layer. With this work, I sought to define the role of increased expression of claudin-2, a protein that regulates sodium flux across intestinal epithelium, in colitis and to investigate whether it can be regulated to alter disease development and progression.;I have discovered that claudin-2 expression during colitis is required to increase stool sodium and water content, driving diarrhea. This flushing response may be critical for expulsion of pathogens from the intestine during inflammation. Complete loss of claudin-2 resulted in development of colonic obstruction in colitic mice, suggesting that complete blockage of the claudin-2 pore function is detrimental. I have also discovered that a pharmacological inhibitor of casein kinase 2, previously shown to regulate the pore pathway in a claudin-2-dependent manner, can reduce diarrhea, weight loss, and the clinical symptoms of colitic mice. In an acute epithelial damage model, CK2 inhibition resulted in preservation and/or increased restitution of the epithelium through a claudin-2-independent mechanism. These findings suggest that CK2 inhibitors may be used as a therapeutic in both chronic diarrhea mediated by claudin-2 and in the setting of acute epithelial damage. The findings presented here have furthered our understanding of the importance of the tight junction proteins in the development of intestinal disease and have revealed that the tight junction can be pharmacologically regulated to alter disease development and progression.