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MRC DiMeN Doctoral Training Partnership: The direct effect of statins on cardiovascular function

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  • Full or part time
    Dr M Cross
    Prof J Schneider
    Prof H Poptani
    Dr B Wilm
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Cardiovascular disease (CVD) is the leading cause of death in the western world. The incidence and prevalence of CVD is highest among the elderly due to the deleterious effects of advancing age on the heart and blood vessels1. Statins are a class of drugs which inhibit the enzyme HMG-CoA reductase leading to reduced cholesterol biosynthesis in the liver and a lowering of plasma LDL-cholesterol levels, ultimately reducing atherosclerosis in patients. In addition to their effects on cholesterol in the liver, statins are known to have positive pleiotropic effects on cardiovascular function. Previous work has shown that statins are potent activators of ERK5 kinase in cardiac endothelial cells, which regulates tight junction formation and vascular permeability2 and in cardiomyocytes, which may lead to improved mitochondrial function. Our hypothesis is that statin activation of ERK5 in both cardiomyocytes and cardiac endothelial cells improves cardiac function and ultimately protects against cardiac pathologies such as aging. This research could impact on the long-term management of cardiovascular aging in humans.
We have developed a novel in vitro human multicellular cardiac microtissue amenable to long-term studies of cardiovascular function3. The project will utilise this model to analyse the long-term effect of statins on cardiac microtissue analysing functional parameters such as contractility (microelectrode array) and structural parameters such as cellular architecture (Zeiss light sheet microscopy). By comparing a range of different statins we will identify the most cardioselective statin and efficient dosing regimen to progress to an animal study.
The second aim will be to use a C57Bl/6 mouse model to analyse cardiac and vascular performance following statin treatment. Cardiovascular physiology will be monitored by cardiac magnetic resonance imaging (MRI). Structural analysis on fixed cardiac tissue will be perform by using immunofluorescence and transmission electron microscopy (TEM).
This studentship project will provide a comprehensive training in cardiac physiology utilising in vitro 3D microtissue analysis supervised by Dr. Mike Cross based in the MRC Centre for Drug Safety Science (MRC CDSS), University of Liverpool https://www.liverpool.ac.uk/drug-safety/. The project will also involve cardiac imaging at the Centre for Preclinical Imaging (CPI) at the University of Liverpool (https://www.liverpool.ac.uk/translational-medicine/research/centre-for-preclinical-imaging/, under the co-supervision of Prof. Harish Poptani and Dr. Bettina Wilm. Secondments will be undertaken at the Leeds Institute of Cardiovascular and Metabolic Medicine at the University of Leeds (https://medhealth.leeds.ac.uk/info/557/division_of_biomedical_imaging/) under the supervision of Prof Jurgen Schneider (second supervisor). In Leeds, the student will learn how to perform cardiac MRI.

Overall, the student will be trained in advanced in vitro cell models of cardiac physiology and in vivo cardiac imaging in a vibrant research environment at the University of Liverpool supported by a multidisciplinary supervisory team with leaders in the fields of cardiac physiology, regenerative medicine and imaging.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Funding notes
Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: https://goo.gl/8YfJf8
Good luck!

References

1. Constantino, S., Paneni F., and Cosentino, F (2016). Ageing, metabolism and cardiovascular disease. Journal of Physiology 594(8):2061-2073

2. Wilkinson, E.L., Sidaway, J.E., and Cross, M.J. 2018. Statin regulated ERK5 stimulates tight junction formation and reduces permeability in human cardiac endothelial cells. Journal of Cellular Physiology 233(1):186-200

3. Ravenscroft, S.M., Pointon, A., Williams, A.W., Cross, M.J., and Sidaway, J.E (2016). Cardiac non-myocyte cells show enhanced pharmacological function suggestive of contractile maturity in stem cell derived cardiomyocyte microtissues. Toxicological Sciences 152(1) 99-112.



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