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Role of signalling mechanisms regulating salt handling and hypertension via NCC in the distal nephron of the kidney

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  • Full or part time
    Dr A Zdebik
    Dr S Walsh
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

The following UCL IMPACT 3 year studentship is available in UCL’s Department of Neuroscience, Physiology and Pharmacology (NPP) www.ucl.ac.uk/npp wef 1 Oct 2013 (PhD induction programme is mandatory last week of September 2013).

This studentship is unfortunately not available to overseas students. It is funded as a 50/50 split between UCL and St. Peter’s Trust. Please do not apply online to UCL admissions.

Project Title: Role of signalling mechanisms regulating salt handling and hypertension via NCC in the distal nephron of the kidney

IMPACT partners: Anselm A. Zdebik, Stephen B. Walsh

Description of project:
Hypertension affects 1.5 billion people worldwide and is the single greatest factor for premature mortality on the planet. One of the major determinants of hypertension is salt (in the form of sodium) and water retention by the kidney. The distal convoluted tubule (DCT), as one of the final sites of regulated sodium reabsorption in the nephron, reabsorbs sodium via the transporter protein called the sodium chloride cotransporter (NCC). NCC is the target for thiazide diuretics, effective and widely prescribed antihypertensive agents. Inactivating mutations of NCC cause Gitelman syndrome, a salt wasting syndrome characterised by low blood pressure, low serum potassium and alkalosis. Furthermore, there is a mirror image syndrome caused by over-activation of NCC which causes hypertension, high serum potassium and acidosis which is called Familial Hyperkalaemic Hypertension (FHHt). This is caused by mutations in various proteins that regulate the expression and activity of NCC in the DCT cells. Two of these proteins, WNK1 and WNK4, members of the With No Lysine (K) family of kinases are part of a complex cascade of kinases that regulates both the trafficking of NCC to the cell membrane and its activation by phosphorylation. Recently, two more genes have been described that when mutated can cause FHHt; Kelch like 3 (KLHL3) and Cullin 3 (CUL3). The functions of these gene products are unknown, but they are hypothesised to be involved in ubiquitination and therefore act to remove NCC from the DCT cell membrane. NCC activity is known to be regulated by both serum potassium as well as aldosterone concentrations; however the mechanisms are unclear.

We recently showed that the hypertension caused by calcineurin inhibitors (CNIs, drugs that are widely used to suppress the immune system in transplant patients) is due to over-activity of the NCC (Hoorn & Walsh Nature Medicine 2011). This study strongly implicated calcineurin as an upstream regulator of NCC, probably regulating WNK1, WNK 3 and WNK4.

This PhD project aims to further elucidate the molecular mechanism of CNI-induced NCC activation by examining how the co-expression of known regulators of NCC expression interact with NCC in the milieu of CNI administration. We have established co-expression in Xenopus oocytes for NCC and some signalling molecules, and further work will involve a conditional FKBP12 (the target for tacrolimus, a CNI) knockout mouse model, which will be analysed for blood pressure and electrolyte balance. Molecular analysis will include Western blotting and immunohistochemistry for components of distal tubular salt reabsorption, including assessment of their ubiquitination. Participation in other projects such as in-vivo 2-photon imaging in zebrafish, which are easily amenable to genetic manipulation, to assess tubular transport and other aspects of their pathophysiology will be encouraged.

Informal enquiries/further details to: Anselm Zdebik [Email Address Removed] or Ben Walsh [Email Address Removed]
Application procedure: Please send C.V. and personal statement to both above email addresses
Closing date: 30th April, 2013
Shortlisted candidates only will be notified by e-mail, interviews conducted beginning of May.

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