The epithelial sodium channel (ENaC) plays a crucial role in sodium regulation by facilitating sodium detection on the tongue and sodium > reabsorption in the kidney, lung and colon. My research is focused on the allosteric regulation of ENaC. One area of interest is how channel activity is up-regulated by proteases. Two of the subunits are cleaved twice, releasing inhibitory tracts and activating the channel. Using electrophysiology, enzymology and molecular modeling, we are characterizing the sites from which these inhibitory tracts originate and how these tracts influence ENaC behavior. Another area of interest is how sodium down-regulates the channel, a salient feature of the channel that enables reduced sodium reabsorption during times of sodium excess. We are using a modeling and molecular evolution approach to examine where sodium binds and how that translates to channel closure.

In the research laboratory, we are examining factors that regulate kidney (or renal) sodium excretion, with special focus on the epithelial sodium channel (ENaC). Increased ENaC activity reduces the sodium excreted in the urine. Using a combination of electrophysiology, animal modeling, and human clinical data we are exploring the roles played by ENaC in regulating sodium excretion and blood pressure in healthy and diseased kidneys. We are examining whether genetic polymorphisms in the genes encoding ENaC alter blood pressure. In experimental systems, ENaC can be activated by extracellular proteases. We are exploring the importance of proteolytic activation of ENaC in vivo in normal physiology and in diseased kidneys. For example, in nephrotic syndrome, a disorder in which damaged kidneys leak blood stream proteins into the urine, it is possible that blood stream proteases such as plasmin activate ENaC in the kidney, reducing excretion of sodium. We are exploring these and other mechanisms of regulation of ENaC. Finally, because ENaC is also expressed in the lung, colon, tongue, blood vessels and brain, we are examining what physiologic roles ENaC plays in sodium transport in these organ systems.