| Title | Investigating anti-cancer drug induced cardiotoxicity in different cell types of the heart |
|---|---|
| Supervisors | Susan Currie Margaret Cunningham |
| Research Area | Cardiovascular and Metabolic Disease Cell Biology |
| Description | Improvements in anti-cancer therapy over recent years have been shadowed by increasing evidence of toxic side effects of anti-cancer drugs on cardiovascular function. The cellular mechanism(s) of action underlying these toxic effects remain largely unknown and this is a major area of concern for the field of safety pharmacology. This is even more pertinent for patients who may already exhibit signs of compromised cardiovascular function prior to receiving anti-cancer therapy. It seems possible that hearts already subject to pathological remodelling and/or compromised function may be more susceptible to the toxicity of anti-cancer therapy. Improved understanding of how anti-cancer drugs exert their effects on cells of the heart is required in order to design better approaches for treatments that circumvent these off-target toxic effects on the heart. This project will investigate how intracellular calcium signalling is affected by selected anti-cancer agents in both contractile and non-contractile cells of the adult heart. It will be important to identify whether common mechanisms underlying toxicity may exist across different cells of the heart. Primary adult cardiac fibroblasts and myocytes will be isolated from normal rats and rats subjected to cardiac hypertrophy. Drug-induced hypertrophic remodelling will also be performed on cells in culture in line with NC3Rs. Cells will either be maintained in culture or used on the day of isolation to investigate phenotypic and functional differences in response to drug treatment. In particular, transition of fibroblasts to myofibroblasts (an indication of pathological response) will be monitored as well as intracellular calcium responses in both cell types (altered calcium handling is evident in cardiac myocytes following hypertrophic remodelling) and the effects of specific anti-cancer agents will be assessed. A comparison between anthracycline and tyrosine kinase-induced effects will be made with a view to understanding the susceptibility of hearts with pre-existing pathology to anti-cancer agents. Functional assays to assess viability, proliferation and cell-cell communication will be assessed using cells from normal and hypertrophied hearts. Investigations will be performed using an animal model of reactive hypertrophic and fibrotic cardiac remodelling. |
| Techniques Used | In vivo drug administration and echocardiography, immunohistochemistry, tissue and cell imaging, calcium imaging and signalling-based assays, primary cell isolation, protein assays, quantitative immunoblotting, proliferation-based assays |
| References | Curigliano G. et al (2016) Cardiotoxicity of anticancer treatments: epidemiology, detection And Management. CA Cancer J Clin 66, 309-325 Dong J & Chen H (2018) Cardiotoxicity of anticancer agents. Front. Cardiovasc. Med. 5:9 doi:10.3389/fcvm.2018.00009 Mooney L. et al (2015) Effects of acute and chronic sunitinib treatment on cardiac function and CaMKII. Br.J.Pharmacol. 172, 4342-4354 |
| Conditions | Applicants should possess or be about to obtain a 1st class or 2:1 Honours degree or equivalent in a Biological Science in addition to receipt of satisfactory references and an IELTS score of 6.5 where appropriate. |
| Bench Fee | Running costs of £12000 p.a. will be associated with this project in addition to University tuition fees. |
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