EASTBIO: Identifying the involvement of putative stretch-sensitive proteins in blood pressure regulation - a bioinformatics investigation of pregnancy to answer a basic science question.

Supervisors:

Dr Guy S Bewick (University of Aberdeen)
https://www.abdn.ac.uk/people/g.s.bewick

Dr Thomas Wishart (University of Edinburgh)
https://www.ed.ac.uk/roslin/about/contact-us/staff/thomas-wishart

Dr Sohinee Bhattacharya (University of Aberdeen)
https://www.abdn.ac.uk/people/sohinee.bhattacharya

Dr Elaine Collie-Duguid (University of Aberdeen)
https://www.abdn.ac.uk/people/e.collie-duguid

AIM: This project seeks to identify the role of key proteins highly expressed in blood pressure sensing nerve endings (baroreceptors), and the placenta. It will test the hypothesis they are crucial for maintaining normal blood pressure, and identify the cellular signalling cascades by which they act.

Blood pressure regulation is complex and poorly understood. For example, hypertension is the greatest risk factor for premature death worldwide and a leading cause of blindness and dementia. Its prevalence is growing as developing countries adopt western lifestyles.

The cause of hypertension is usually unknown. Current drugs are often ineffective and induce side-effects. Most patients require multidrug treatments, 10-15% are resistant to treatment, while many avoid treatment to avoid the side effects. Conversely, it is unknown how blood pressure falls naturally during early pregnancy, while hypertension can also occur spontaneously (pre-eclampsia), endangering both mother and child.

Clearly, blood pressure regulation is poorly understood. Identifying the roles of putative stretch-sensitive ion channel proteins highly expressed in baroreceptors and placenta will fill an important gap in our knowledge. These channels are members of the DEG/ENaC family - the ENaCs (epithelial sodium channels) and ASICs (amiloride sensitive ion channels). Functioning as heterotrimers, deletions disrupt blood pressure in mice[1] and mutations in individual subunits predispose to hypertension and pre-eclampsia in some ethnic groups[2]. This project will examine worldwide bioinformatics of pregnancy to elucidate relationships between mutations in DEG/ENaC subunits and blood pressure, and their associated signalling pathways.

The successful candidate will,
1) use the latest computing approaches (genetic linkage analysis: searching worldwide anonymised patient data bases, statistical analysis and disease correlation) to identify mutations in these channels linked to hypertension and pre-eclampsia;
2) correlate the channels with associated signalling pathways to identify regulatory mechanisms (pathway analysis); and
3) interrogate anonymised patient databases for the role of these proteins during pregnancy – a unique condition where blood pressure is depressed until the middle of the second trimester (electronic health record analysis).

The student will receive training in cutting edge bioinformatics analysis techniques (big data analysis of GWAS and health records from across the globe), as follows:
1) Genetic linkage analysis: Co-localisation will estimate the genetic correlation between DEG/ENaC protein family members and normal blood pressure.
2) Pathway analysis: Mendelian Randomization will assess causal roles of mutations in these proteins in the development of hypertension and pre-eclampsia. Then, Pathway Analysis will elucidate the signalling cascades underlying genetic associations between these proteins and blood pressure.
The above aims leverage data from the world’s largest genome-wide association study (GWAS) of infants and mothers affected by pre-eclampsia[3]. We have exclusive access to these unpublished results.

A final aim is:
3) Data Linkage: Large-scale data linkage and electronic health record analysis will evaluate the role of these proteins in blood pressure during pregnancy as normal and dysregulated changes occur.
This aspect takes advantage of our access to large-scale electronic health record datasets.

This project is based predominantly in Aberdeen, with expert training in bioinformatics, biostatistics, epidemiology and proteomic analysis at Aberdeen, Edinburgh and Cambridge Universities.

Application Procedure:
http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO application form, along with academic transcripts and CV to Alison McLeod at [Email Address Removed]. Two references should be provided by the deadline using the EASTBIO reference form. Please advise your referees to return the reference form to [Email Address Removed].