Background: Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Cardiomyocytes rely on specialised metabolism to meet the high energy demand of the heart. During differentiation of pluripotent stem cells into cardiomyocytes their metabolism matures, however, cardiac diseases such as heart failure secondary to myocardial infarction are characterised by perturbed metabolism with a shift towards immature metabolism. This proposed PhD project will use state-of-the art techniques to generate human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) and fibroblasts (hiPSC-FBs) to investigate the role of metabolism in various cardiac disease models.
Aims To model and investigate changes that occur in cardiovascular disease states using hiPSC-CMs and hiPSC-FBs with particular focus on metabolism of cardiac cells to gain knowledge of disease mechanisms, and to evaluate novel pharmaceutical treatment strategies.
Methods: Gene edited hiPSC lines will be differentiated into contractile beating cardiomyocytes and secretory active cardiac fibroblasts. Either in isolation or in co-culture, these cells will be exposed to various stressors to model cardiovascular disease. The models will be validated and interrogated to understand the changes that occur under these stressors. A range of state-of-the art laboratory techniques and methods will be used to investigate the cells, including cell viability and proliferation assays, immunohistochemistry, as well as functional assessment of contractility and metabolism (Seahorse and Metabolic assays). Gene expression and protein expression analysis using reverse transcription polymerase chain reaction (qRT-PCR) and western blotting, respectively, will be utilised to investigate the pathways involved. Mass spectrometric and proteomics analysis will be used to disentangle the underlying mechanisms further.
Training: As well as the specific technical training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide range of seminars and training opportunities setting them up for a future in science.
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