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Dr K O'Shaughnessy
No more applications being accepted
Funded PhD Project (European/UK Students Only)
About the Project
The Department of Medicine is seeking applications from eligible students who wish to undertake an MRC-funded 3 year PhD studentship starting October 2012. The five research projects available, together with supervisor details, can be found on the Departments website at: http://www.med.cam.ac.uk/mrc-phd-studentship-2012-project-outlines/
It has recently been reported that a rare monogenic syndrome with hypertension and massive adrenal adenomas (type III familial hyperaldosteronism) is caused by germ line mutations in the KCNJ5 K channel Science 2011;331(6018):768-72. It also transpires that sporadic Conn’s adenomas frequently carry similar somatic KCNJ5 mutations. We have now confirmed this in a large cohort of sporadic aldosteronomas from Cambridge and Brisbane Australia (Hypertension 2012, in press copy attached and further submission). However, it is not clear how these mutations in the selectivity filter of the KCNJ5 channel affect aldosterone release and whether they are important in the molecular pathogenesis of Conn’s tumours. The project will directly address these issues making extensive use of an established adrenal cortical cell line H295R (although we are looking at developing a transgenic mouse if BHF funding applications are successful). We have worked extensively with the H295R and are currently looking at the patch clamp behaviour and aldosterone release from H295R cells expressing mutant KCNJ5 channels. The student would build on this work and also look at the response of these mutant channels to channel inhibitors. We have show early data suggesting they are relatively resistant to tertiapin, which is consistent with the proximity of its binding site to the mutated inner pore region of the mutant KCNJ5 channels. They will also investigate the possibility that the KCNJ5 mutants cause a direct growth stimulus by Ca-loading of the adrenal cortical cells. Evidence of activated growth pathways will also be sort by expression profiling cells stably expressing mutant KCNJ5 channels. We have preliminary evidence that tumours with KCNJ5 mutations have a definite phenotype-genotype correlation (loss of the postural response to standing and ZF-predominant cell type histology). The project will follow this lead looking for evidence of a ZF gene expression signature in these stable cell lines. Overall, this area is evolving rapidly and is certain to add very significantly to our molecular understanding of the Conn’s tumour. It is no longer seen as a rare curiosity but a treatable form of hypertension in probably 1-2 % of essential hypertensives.
Post short-list enquiries can be made to Professor Edwin Chilvers ([Email Address Removed]).
Fixed-term: The funds for this studentship are available for 3 years in the first instance.
The University values diversity and is committed to equality of opportunity. The University has a responsibility to ensure that all employees are eligible to live and work in the UK.
Applicants should submit a full CV, including details of two referees, and a covering letter clearly indicating which of the projects they are interested in to Mrs Linda Whyles via email: [Email Address Removed].
Applications must be received by 5pm on the closing date.
Quote reference: RC00092, Closing date: 19 February 2012.
It has recently been reported that a rare monogenic syndrome with hypertension and massive adrenal adenomas (type III familial hyperaldosteronism) is caused by germ line mutations in the KCNJ5 K channel Science 2011;331(6018):768-72. It also transpires that sporadic Conn’s adenomas frequently carry similar somatic KCNJ5 mutations. We have now confirmed this in a large cohort of sporadic aldosteronomas from Cambridge and Brisbane Australia (Hypertension 2012, in press copy attached and further submission). However, it is not clear how these mutations in the selectivity filter of the KCNJ5 channel affect aldosterone release and whether they are important in the molecular pathogenesis of Conn’s tumours. The project will directly address these issues making extensive use of an established adrenal cortical cell line H295R (although we are looking at developing a transgenic mouse if BHF funding applications are successful). We have worked extensively with the H295R and are currently looking at the patch clamp behaviour and aldosterone release from H295R cells expressing mutant KCNJ5 channels. The student would build on this work and also look at the response of these mutant channels to channel inhibitors. We have show early data suggesting they are relatively resistant to tertiapin, which is consistent with the proximity of its binding site to the mutated inner pore region of the mutant KCNJ5 channels. They will also investigate the possibility that the KCNJ5 mutants cause a direct growth stimulus by Ca-loading of the adrenal cortical cells. Evidence of activated growth pathways will also be sort by expression profiling cells stably expressing mutant KCNJ5 channels. We have preliminary evidence that tumours with KCNJ5 mutations have a definite phenotype-genotype correlation (loss of the postural response to standing and ZF-predominant cell type histology). The project will follow this lead looking for evidence of a ZF gene expression signature in these stable cell lines. Overall, this area is evolving rapidly and is certain to add very significantly to our molecular understanding of the Conn’s tumour. It is no longer seen as a rare curiosity but a treatable form of hypertension in probably 1-2 % of essential hypertensives.
Post short-list enquiries can be made to Professor Edwin Chilvers ([Email Address Removed]).
Fixed-term: The funds for this studentship are available for 3 years in the first instance.
The University values diversity and is committed to equality of opportunity. The University has a responsibility to ensure that all employees are eligible to live and work in the UK.
Applicants should submit a full CV, including details of two referees, and a covering letter clearly indicating which of the projects they are interested in to Mrs Linda Whyles via email: [Email Address Removed].
Applications must be received by 5pm on the closing date.
Quote reference: RC00092, Closing date: 19 February 2012.
Funding Notes
Eligible students will hold a 2(i) class degree and/or a Masters level qualification in a relevant subject. The studentship will cover student stipend, PhD fees and college membership and is available to UK and EU students only. If a student is from an EU country, but cannot demonstrate a relevant connection to the UK through ordinary residence, they may be eligible for a studentship for tuition fees, but not for a maintenance stipend. Non-EU or overseas citizens are not eligible and need not apply.
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