We focus primarily on mechanisms of microbial pathogenesis, innate mechanisms of host defense in the human intestine, and on the mechanisms and regulation of ion transport responsible for secretory and inflammatory diarrheas.
In the cholera toxin project, we study how cholera toxin produced by V. cholerae breeches the intestinal epithelial barrier and enters host epithelial cells to cause disease. We have discovered how the enteric bacterial toxin, cholera toxin (CT), breeches the intestinal epithelial barrier and enters host epithelial cells to cause disease. CT and the other AB5-subunit toxins hijack membrane lipids and the cellular and molecular mechanisms of retrograde membrane transport to move from the plasma membrane into the endoplasmic reticulum (ER) of affected cells. Once in the ER, a portion of the toxin, the A1-chain, co-opts components of ERAD (ER-associated degradation) to retro-translocate to the cytosol where it acts enzymatically to cause disease. Recent studies show that the structure of the ceramide (lipid) domain of the GM1 slycophingolipid receptor plays a decisive role in the trafficking of the toxins backwards in the secretory pathway. Structure-function analysis have elucidated native and non-native ceramide domains that may have clinical applications.
In the Fcg-receptor FcRn project, the lab studies the cell and molecular biology of transcytosis by the MHC Class I-like IgG receptor FcRn. FcRn transports IgG across mucosal surfaces where it may function in immune surveillance and host defense. The transcytotic pathway across barrier epithelial cells is not well studied though it provides a critical link between the outside (microbial) and inside (sterile) worlds of the gut (and lung).
In a third area of interest, we aim to understand the regulation of ion and water transport in the intestine. These studies address the biology of several ion transporters responsible for secretory diarrhea. Other aspects of epithelial cell biology unique to the intestinal mucosa, such as the cell biology of genes implicated in the inflammatory bowel diseases, are also studied.
My work in each of these areas has led to 15 patent awards. The FcRn research program led to the founding of a Biotech company that was acquired by Biogen Idec and two novel biologics now FDA approved: Alprolix and Eloctate for treatment of hemophilia A and B.