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Investigating metabolism in cardiac disease using human pluripotent stem cells


   Norwich Medical School

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  Dr J Smith  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

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. 


Funding Notes

This PhD project is a Faculty of Medicine and Health Sciences competition for funded studentships. The studentships are funded for 3 years and comprise UK tuition fees, an annual stipend of £15,609 (2021/22 rate) and £1,000 per annum to support research training. International applicants (including EU) may apply but are required to fund the difference between UK and International tuition fees (details of tuition fees can be found on our website https://www.uea.ac.uk/study/fees-and-funding/fees).

References

Bhagwan, J. R., et al. (2020). Isogenic models of hypertrophic cardiomyopathy unveil differential phenotypes and mechanism-driven therapeutics. Journal of Molecular and Cellular Cardiology. 145, p. 43-53 11 p.
Smith, J. G. W., et al. (2018). "Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits." Stem Cell Reports 11(5): 1226-1243.
Mosqueira, D., et al. (2018). "CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy." Eur Heart J 39(43): 3879-3892.
Kondrashov, A., et al. (2018). "Simplified Footprint-Free Cas9/CRISPR Editing of Cardiac-Associated Genes in Human Pluripotent Stem Cells." Stem Cells Dev 27(6): 391-404.

Reinhold, J., et al. (2021). “Iron deficiency for prognosis in acute coronary syndrome - A systematic review and meta-analysis.” Int J Cardio 328:46-54.
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