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MRC DiMeN Doctoral Training Partnership: Understanding how changes in cardiovascular ageing in patients treated with chemotherapy leads to long-term cardiovascular damage and disease in 1-in-10 cancer survivors


   MRC DiMeN Doctoral Training Partnership

  , Dr Richard Rainbow  Friday, January 14, 2022  Competition Funded PhD Project (Students Worldwide)

Liverpool United Kingdom Cancer Biology Cardiology Cell Biology Molecular Biology Pharmacology Physiology Toxicology

About the Project

Background

Cardiovascular disease is the number one non-cancer cause of death in cancer survivors, attributable to side-effects of cancer medications routinely given to patients. Anthracyclines are chemotherapeutic drugs known to cause dose-dependent cardiac damage leading to heart failure in 10% of cancer patients. Incomplete mechanistic insight means we are unable to predict or prevent this from occurring. A lack of preventative measures has come primarily from the unavailability of human tissue.

This PhD study will overcome this limitation by using cutting-edge techniques that generate induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) from blood samples of patients diagnosed with drug-induced cardiotoxicity and those with damage-resistance.

An acceleration of cellular ageing is one of the proposed, yet understudied, mechanisms that may lead to cardiovascular disease attributed to the side-effects of oncology therapeutics.

Aim

This PhD project aims to understand the cardiovascular damage caused by chemotherapy and to identify how premature cardiovascular ageing may be contributing to long-term damage in cancer survivors. We will further investigate if modulation of the NRF2 pathways reduces the rate of ageing in our healthy and drug-induced models.

Methods

We have stem cells in place from patients who have suffered from oncology drug-induced cardiotoxicity and those on matched treatments who do not suffer from cardiac dysfunction. These will be differentiated into beating cardiomyocytes that recapitulate the donor’s primary cardiomyocyte phenotype. Cells will be validated and analysed to understand the differences between the two populations of patients using a multi-disciplinary approach. We will delineate the ageing process tracking known cell ageing markers as well using our cutting-edge 3D multi-cellular heart model to monitor the appearance of fibrosis. We will also perform proteomic and electrophysiology studies over several weeks to understand new pathways and electrical changes involved in cardiovascular ageing over time. We will further investigate if stimulation of the NRF2 pathway reduces the amount of damage caused by chemotherapy and hence the rate of cellular ageing.  

Together, this will form the first comprehensive study of cardiac ageing in a human in vitro model. 

Student experience

With cancer survival statistics on the rise, oncology patients in remission are at high risk of becoming cardiology patients. The cutting-edge technology utilised in this studentship, coupled with world-leading equipment and facilities brings together a unique opportunity for you to generate fundamental mechanisms and predicative tools with innovative strategies to prevent, predict and diagnose cardiovascular damage.

You will join a vibrant, multidisciplinary group in collaboration with cardiologists and oncologists. You will gain training in a multitude of techniques, ranging from 2D and 3D cell culture, iPSC generation and differentiation, electrophysiology measurements as well as specialized techniques including liquid chromatography mass spectrometry (LC/MS) using in-house mass spectrometers, proteomic analysis, data handling and statistics to evaluate global changes and biomarker release upon drug administration. Validation of differentially expressed proteins will establish skills including siRNA transfection, western blotting, immunofluorescence and ELISA. This will ensure a well-rounded training environment with a multitude of transferable skills forming the groundworks of a successful independent scientist.

Supervisor websites

https://www.liverpool.ac.uk/life-course-and-medical-sciences/staff/parveen-sharma/

https://www.liverpool.ac.uk/life-course-and-medical-sciences/staff/richard-rainbow/publications/

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, York 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 and how to apply can be found on our website:

http://www.dimen.org.uk/how-to-apply/application-overview


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover UK tuition fees, stipend and project costs as standard. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will be awarded to exceptional candidates only, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2022
Good luck!

References

Tomlinson et al Attenuation of doxorubicin-induced cardiotoxicity in a human in vitro cardiac model by the induction of the NRF-2 pathway, Biomedicine & Pharmacotherapy (2019) https://doi.org/10.1016/j.biopha.2019.108637.

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