Research Abstract

My laboratory studies the cell and molecular biology of vesicular transport and a novel mechanism of innate immunity unique to the polarized epithelial cells that line mucosal surfaces.These projects relate to how barrier epithelial cells interact with the luminal and sub-epithelial microenvironment, and to the biology of bacterial pathogenesis and mucosal host defense.

We have discovered how some enteric bacterial toxins breech the intestinal epithelial barrier and enter host epithelial cells to cause disease. These toxins hijack the cellular and molecular mechanisms of retrograde membrane transport to move from the luminal cell surface into the endoplasmic reticulum (ER), where they hijack the mechanics of ER Associated Degradation to enter the cytosol,almost the total reverse of protein biosynthesis.

We also recently discovered how the cell senses such invasion via the most ancient sensor ER stress – IRE1. Signal transduction originates in the ER lumen (previously thought to be devoid of pattern recognition molecules) and is transduced to both NFκB and IFN via the viral sensor RIG-I. The pathway is amplified at mucosal surfaces.

In another project, the lab studies the cell and molecular biology of transcytosis by the MHC Class I-like IgG receptor FcRn and the glycosphingolipid GM1. FcRn transports IgG across mucosal surfaces where it may function in immune surveillance and host defense. A new translational project tests if lipid sorting for GM1 can be applied clinically as a platform for biologic-drug delivery.

My work in each of these areas has led to over 14 patent awards. The FcRn research program led to the founding of a Biotech company that was acquired by Biogen Idec and we now have two novel biologics FDA approved.