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Group Staub

Olivier Staub, Associate Professor

Olivier Staub received his bachelor degree (chemistry) at the University of Bern, Switzerland (1987), and his PhD degree at the University of Lausanne (1992). He was then trained as a postdoc at UCLA and at the Hospital for Sick Children in Toronto, before joining the Department of Pharmacology & Toxicology as an independent researcher in 1997. Currently he holds the position of an Associate Professor.

Keywords: Na+-homeostasis, hypertension, ion channel, protein-protein interaction, ubiquitylation, phosphorylation,

We are interested in the physiological and pathophysiological role of ubiquitylation in the control of Na+ balance and blood pressure. This regulation involves the epithelial Na+ channel ENaC in the distal nephron, a channel that is tightly governed by hormones including aldosterone, vasopressin and insulin. Our work has demonstrated that some of the involved regulatory pathways involve modulation of the ubiquitylation level ENaC via the ubiquitin-protein ligase Nedd4-2, thereby reducing ENaC density at the cell surface. In Liddle's syndrome, an inherited disease of salt-sensitive hypertension, the regulation by Nedd4-2 is impaired, causing constitutive Na+-reabsorption via ENaC and consequently hypertension. Recently the role of Nedd4-2 in the control of blood pressure has been validated in a Nedd4-2 KO mouse. The Nedd4-2 dependant regulation of ENaC is regulated by various pathways, including the phosphorylation by the aldosterone-inducible Sgk1 kinase, by the aldosterone dependant deubiquitylating enzyme Usp2-45 and by salt dependant variation in the expression of Nedd4-2. We are investigating these regulatory mechanisms, both in vitro and in vivo, using different models including Xenopus laevis oocytes, epithelial and non-epithelial cell lines and novel transgenic mouse models. Techniques include molecular biology, biochemistry, cell biology, renal physiology and electrophysiology.

figure.jpg

Regulatory pathways controlling Nedd-42 dependant ubiquitylation and internalization/degradation of ENaC. High sodium diet increases Nedd4-2 expression in the cortical collecting duct. Aldosterone increases Sgk1 and Usp2-45 expression, and consequently interferes with ENaC deubiquitylation. Deubiquitylation also favors proteolytic cleavage and activation of ENaC.


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