University of Pittsburgh

My laboratory seeks to elucidate the kidney’s role in blood pressure and potassium homeostasis. A major focus of our work concerns the regulation of sodium chloride reabsorption in the distal nephron by With-No-Lysine (WNK) kinases, a unique family of serine threonine kinases implicated in the coordination of renal NaCl reabsorption and K+ secretion. We have provided key evidence demonstrating that the WNK kinases participate in a signaling pathway that modulates the trafficking of the thiazide-sensitive sodium chloride cotransporter (NCC). We are actively investigating how hormones that regulate blood pressure interface with the WNK signaling pathway to influence NCC localization, phosphorylation state, and turnover. A second area of research concerns the molecular basis of Gitelman syndrome, a Mendelian salt wasting disorder caused by loss-of-function mutations of NCC. In most cases, these mutations cause the cotransporter to misfold, resulting in the activation of endoplasmic reticulum quality control mechanisms that target NCC for proteasomal degradation. We have identified a complex of molecular chaperones that sense the conformational status of NCC, and are beginning to evaluate how these proteins interact differently with NCC mutants that give rise to human disease. Our ultimate goal is to make new discoveries in these areas of investigation at the cellular and molecular level, linking fundamental aspects of cellular biology to clinically relevant renal physiology and human disease. To this end, we employ techniques from a variety of disciplines to test our hypotheses, including molecular biology, protein biochemistry, cell biology, and cellular and whole animal physiology.