Welcome to the Harvey Laboratory
Our goal is to understand how solutes move into and out of epithelial cells. We study how animals take up nutrient amino acids and ions, such as Na+, K+ and Cl-, from the digestive tract while regulating pH. In the pre-genomic era the highly alkaline caterpillar midgut served as a model. We isolated and characterized a 14-subunit proton-translocating, membrane protein called a vacuolar-type ATPase (H+ V-ATPase). The ATPase protein imposes across midgut epithelial cell membranes a voltage that drives ion exchange and nutrient uptake via other proteins called transporters. In the post-genomic era we developed a new model - the larval midgut of the African malaria mosquito, Anopheles gambiae. Using the Anopheles mosquito genome we have cloned seven amino acid transporters and several salt transporters. Of special interest is a Na+/H+ antiporter (NHA) that moves H+ into cells and Na+ out of them, driven by the voltage from the H+ V-ATPase; we call it AgNHA1. The An. gambiae midgut is becoming a model for solute transport in mosquito larvae with broad implications for transport across epithelia in human kidney, eye, bone and other organs.
Presently, we are studying a new type of Na+/H+ exchanger (NHE). Classical NHEs use inward Na+ gradients to drive Na+ into cells and metabolically produced H+ out of them. We propose that when H+ V-ATPase drives H+ out of cells, the resulting voltage drives Na+ coupled to an amino acid into cells via a Na+ amino acid transporter (NAT). Thus H+ V-ATPases and NATs together function like NHEs; we call them NHEVNATs. We are also studying a paradox in which voltages and pH differences drive ATP synthases in alkalophylic bacteria, solute transporters in mammalian small intestine and K+ or Na+ antiport in the midgut of caterpillars and larval mosquitoes, even though the external H+ concentration is low (pH is high) in all three cases. We propose that H+s from electron transport in bacteria, NHE activity in mammals and H+ V-ATPase activity in insects, respectively; remain in a boundary layer outside the membrane thereby providing a high H+ concentration source for the H+ -linked transporters even though the bulk H+ concentration is low.
Finally, we are responding to the Graham/Talent Committee finding that bioterrorism is more of a threat to homeland security than the atom bomb. We formed "Operation Stop Pandora" to counter a release of mosquitoes carrying yellow fever or other tropical diseases by bioterrorists. Sponsored by the Emerging Pathogens Institute and the Bob Graham Center we are arranging an anti-bioterrorist workshop comprising experts from mosquito control centers, the USDA and other organizations.
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