Phospholipase C (PLC) and Regulation of Epithelial Paracellular Permeability

Phospholipase C (PLC) and Regulation of
Epithelial Paracellular Permeability

Ryan’s research interests include understanding mechanisms of drug transport across cellular barriers, the role of intestinal and hepatic metabolism in limiting oral drug absorption, and developing strategies to increase drug transport and oral absorption.  His dissertation research has focused on understanding the role of the signal transduction enzyme, phospholipase C, in regulating the barrier function of epithelial tight junctions. The identification of a protein that controls epithelial paracellular permeability would allow the rationale design of drugs as intestinal paracellular permeability enhancers (PPEs).

Previous studies from the Thakker laboratory suggest that chemical inhibition of PLC in MDCK II cells leads to an increase in paracellular permeability by specific modulation of tight junctions. These studies implicate signaling pathways emanating and converging on PLC in regulating the barrier function of epithelial tight junctions. The direct application of these data to human intestinal absorption is unknown however, due to the canine kidney origin of MDCK cells. Ryan’s work has extended the hypothesis to human intestinal absorption by establishing that chemical inhibition of PLC in Caco-2 cells, an immortalized human intestinal cell line, is similarly associated with increased paracellular permeability. Ryan is currently collaborating with Dr. James Anderson’s laboratory in the Department of Cell and Molecular Physiology in the UNC School of Medicine, applying alternative approaches, such as RNA interference, to reduce the expression and activity of specific PLC isozymes in order to confirm the proposed hypothesis that PLC isozymes regulate tight junction function.