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Cardiotoxicity of cancer drugs targeting the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

About This PhD Project

Project Description

"Heart failure is a leading cause of morbidity and mortality worldwide. The contractile cells of the heart, cardiomyocytes, possess many protective mechanisms, allowing them to withstand pathophysiological stresses. However, they are terminally-differentiated and do not divide after birth. In response to hypertension, cardiomyocytes undergo hypertrophic growth (i.e. increase in size in the absence of cell division) in order to increase cardiac output. Following a myocardial infarction (heart attack) cells in the ischaemic area die and, to maintain cardiac function, surviving cells hypertrophy. The hypertrophic response can maintain a ""compensated"" state in the short term, but may degenerate as protective mechanisms fail, leading to heart failure. Increasing cardioprotective mechanisms, whilst inhibiting destructive mechanisms is therefore desirable.

Protein kinase signalling plays a pivotal role in modulating the balance between cell survival and cell death. The ERK1/2 cascade is generally recognised for its effects in promoting cell proliferation and cell survival which is why drugs have been developed to inhibit the pathway for the treatment of cancer. In cardiomyocytes, ERK1/2 signalling is associated with hypertrophy and cell survival, and inhibitors of ERK1/2 signalling have a detrimental effect on the heart in some patients.

This project will explore the effects of inhibitors of ERK1/2 (e.g. ulixertinib, GDC-0994) and MEK1/2 (upstream kinases that activated ERK1/2) inhibitors (trametinib, cobimetinib) on cardiomyocytes and the heart under basal conditions and in the context of pathophysiological stresses (e.g. oxidative stress or hypertension). We will use in vivo mouse models, in addition to ex vivo (perfused hearts) and in vitro (cells in culture) systems. A range of biochemical, cell biology and molecular biology techniques will be used (e.g. quantitative PCR, western blotting, primary cell culture, immunofluorescence microscopy, protein kinase assays etc.).

Work experience in a molecular biology laboratory would therefore be useful, but training in all techniques can be provided.

Training will be provided specifically for heart research systems (primary cultures, ex vivo heart perfusions, in vivo assessment of heart function). An interest in intracellular signalling and understanding of cell biology/biochemistry is important. The position would suit an individual with a particular interest in biomedical research and would be ideally suited to individuals with an interest in the development of heart failure.

"

References

Abdel-Rahman O, ElHalawani H, Ahmed H. J Glob Oncol. 2015 Nov 25;1(2):73-82. doi: 10.1200/JGO.2015.000802. eCollection 2015 Dec.; Sullivan et al. Cancer Discov. 2017 Dec 15. doi: 10.1158/2159-8290.CD-17-1119. [Epub ahead of print].; Blake et al. J Med Chem. 2016 Jun 23;59(12):5650-60. doi: 10.1021/acs.jmedchem.6b00389.; roskoski Pharmacol Res. 2017 Mar;117:20-31. doi: 10.1016/j.phrs.2016.12.009.

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