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Research Interest

The major focus of the Moe laboratory is to study the mechanisms of regulation of the principal sodium transporter in the kidney, Na/H exchanger type 3 (NHE3). Normal NHE3 function and regulation are essential for the maintenance of normal extracellular fluid volume, blood pressure and acid-base balance. All the following projects are currently involving or will involve trainees:

  • Regulation of NHE3. Role of protein trafficking. NHE3 can be acutely regulated by alterations in endocytotic retrieval or exocytotic insertion into the membrane. We are currently studying the regulation of both of these trafficking events. We have recently uncovered a non-genomic mechanism of activation of NHE3 by glucocorticoid hormones through NHE3 exocytosis.
  • Regulation of NHE3.Role of phosphorylation and binding proteins. Phosphorylation of NHE3 is necessary but insufficient to affect its regulation. We propose that regulatory cofactors are crucial to modulate the phosphorylated protein. We are using multiple approaches to isolate these protein factors. The figure shows one such interacting partner which is calcineurin homologous protein (CHP). CHP-1 interacts with NHE3 and is responsible for mediating the regulation of NHE3 by adenosine.
     
  • Regulation of NHE3. Role of membrane lipids. In collaboration with the laboratory of Don Hilgemann, we have developed a novel electrophysiologic method to assay Na/H exchange. Using this method, we are examining the role of membrane lipids in the regulation of NHE3.
  • Regulation of NHE3 translation. NHE3 is regulated at the translation level by a variety of agonists including dopamine and glucocorticoids. We will define cis-elements in the 5'-untranslated region of the NHE3 transcript that confer this type of regulation.
  • Regulation of NHE3 degradation. NHE3 protein is degraded by both the lysosomal and proteasomal pathways. We are currently studying how NHE3 degradation via these pathways is regulated.
  • Regulation of NHE3 in renal ischemia. Na/H exchanger NHE3 expression virtually disappears with ischemia-reperfusion injury and is increased during recovery. We are studying the mechanisms of suppression and activation of NHE3 expression in ischemia-reperfusion injury.

In addition to NHE3, the laboratory is also studying other areas that are complementary to some of the clinical projects that are under the same P.I.:

  • Regulation of proximal tubule glycolysis in renal ischemia. The proximal tubule is normally an aerobic tissue with an enormous dormant glycolytic reserve. This reserve is rapidly activated upon ischemia. We are currently studying the role of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in mediating the recruitment of glycolytic reserve.
  • Insulin signaling in the kidney and regulation of renal ammoniagenesis and transport by insulin. The renal effects of insulin are not well defined. Our group recently identified impairment in renal ammonium and uric acid excretion as potential renal manifestations of insulin resistance. Complementary to the clinical efforts are laboratory studies designed to elucidate the mechanisms by which insulin regulates renal ammonium and uric acid excretion.
  • Functional and structural characterization of the soluble adenylyl cyclase. The recently discovered soluble adenylyl cyclase is a bicarbonate sensor. We have identified that certain base changes of this gene are associated with disturbances in calcium metabolism. We are studying the function of the wild type and mutant soluble adenylyl cyclase to clarify its role in calcium metabolism in the bone, gut, and kidney.