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Mechanistic understanding of cancer drug induced cardiotoxicity using patient derived induced pluripotent stem cell (iPSC) derived cardiomyocytes


   Institute of Life Course and Medical Sciences


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 adults and result in a 15-fold higher risk of congestive heart failure in paediatric patients.

However, we are still unable to predict which patients will develop cardiac complications or understand fully why this occurs. Mechanistic insight required to drive clinical practice for protecting patients is primarily hindered due to the lack of donor heart tissue from a non-regenerative organ. The proposed study will overcome this limitation by using cutting-edge techniques that generate induced pluripotent stem cell derived cardiomyocytes from blood samples of patients diagnosed with drug-induced cardiotoxicity and those with damage-resistance.

Aim

To understand the cardiovascular damage caused by chemotherapy and to identify early diagnostic biomarkers that will allow for the identification of patients before irreversible damage is done to their heart.

Methods

Blood samples and clinical data will be obtained from adult breast cancer and lymphoma patients receiving anthracycline therapy with diagnosed cardiac dysfunction, and breast cancer and lymphoma patients on matched anthracycline therapy without cardiac dysfunction. Blood cells will be reprogrammed into induced pluripotent stem cells (iPSC) using novel, integration-free Sendai-viral transduction. These will be differentiated into beating cardiomyocytes (iPSC-CM) 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, including evaluation of standard cell health parameters, differential protein expression by mass spectrometry and proteomics to understand pathway changes, metabolic changes via mass spectrometry-based metabolomics, and structural changes through immunofluorescence. Functional changes will be examined via standard patch-clamp electrophysiology techniques coupled with Ca2+-fluorescence measurements to understand ion channel and Ca2+ changes in the heart.

Samples obtained in this study will also be used to conduct proteomics and mass-spectrometry based metabolomics on plasma obtained patient diagnosed with drug-induced cardiotoxicity and those with damage-resistance to determine differential expression in plasma proteins and metabolite signature giving insight into cell damage pathways and allowing identification of potential cardiac damage biomarkers.

Student experience

With cancer survival statistics on the rise, yesterday’s oncology patients are becoming tomorrow’s cardiology patients. This cutting-edge technology utilised in this studentship, coupled with world-leading equipment and facilities brings together a unique opportunity for a student to generate fundamental mechanisms and predicative tools with innovative strategies to prevent, predict and diagnose cardiovascular damage.

The successful student 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 Orbitrap QExactive mass spectrometer (UoL) and proteomic analysis using tools such as Ingenuity which will be used to evaluate global changes and biomarker release upon drug administration. Validation of biomarkers and differential expressed proteins will establish skills including western blotting, immunofluorescence and ELISA.

Research Environment

The research outlined will be carried out in Department of Cardiovascular and Metabolic Medicine (CMM) at the University of Liverpool, which works synergistically with the Liverpool Centre of Cardiovascular Science (LCSS). This unique environment will allow any potential student to use clinical expertise in tandem with fundamental science to tackle a global problem. We will have access to patient samples through our unique consortium of cardiologists, oncologists and academics from the Liverpool Heart and Chest Hospital Cardio-oncology Clinic https://www.lhch.nhs.uk/news-archive/2019/november/patients-to-benefit-from-new-cardio-oncology-service/ and Clatterbridge Cancer Centre https://www.clatterbridgecc.nhs.uk/. The UoL and LCCS which have formed a cross-cutting cardio-oncology research theme to investigate drug-induced cardiotoxicity. The Centre has various global health initiatives including cardio-oncology and the student will benefit from regular meetings with experts where they will be expected to provide regular updates of their progress. Working within this interdisciplinary centre will give the student a distinctive outlook in biomedical research and their training in novel techniques.

We are looking for a highly motivated student who is willing to pursue cutting edge research within a vibrant and collegiate team. Candidates with good communication skills and experience in molecular biology, biochemistry and stem cell biology are encouraged to apply. Training in laboratory techniques would be provided where necessary. A BSc/MSc/MRes in biology/biomedical sciences, physiology, pharmacology, or a health-related subject would be essential.

For any enquiries, please contact Dr Parveen Sharma on:

Application is by CV and covering letter.  The covering letter must detail your interest in the studentship, related experience and training and suitability for the position.  Applications should be sent to Dr Parveen Sharma


Funding Notes

We are looking for self-funded students or students who have secured funding from an independent body. There is no financial support available from Liverpool for this study. Please see website for PhD student fees at the University of Liverpool View Website.
The successful applicant will be expected to have funding in place for the tuition fees (check University of Liverpool website), consumables/bench fee (£ 16000 per annum) and living expenses during their stay in Liverpool.

References

1. Tomlinson et al 2019 Biomed Pharmacother 2019 Apr;112:108637. doi: 10.1016/j.biopha.2019.108637.
2. Herrmann 2020 Nature Revs Cardiology 17, pages474–502(2020). doi.org/10.1038/s41569-020-0348-1

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