About the Project
The use of human induced pluripotent stem cells (hIPSCs) in modelling cell response to drugs is an area of research that is growing rapidly and is of global significance. In the past some drugs that were thought to be safe during their development went on to cause serious heart problems and even fatalities when prescribed to patients. Harmful drugs were found to stop the heart from functioning properly by altering the control of electrical activity and energy metabolism required for the force generating cells of the heart (cardiomyocytes) to function, and ultimately the ability of the heart to beat properly. Drug development is therefore heavily dependent on animal testing to ensure that they are safe and effective for people to use. However, differences in the biology of humans and animals means that these tests are not always accurate. Cardiotoxic effects that are missed in animal studies can go on to affect human patients or else drugs that have a cardiotoxic effect in animals can be discarded when they don’t provoke the same response in humans. There is therefore an urgent need to develop humanised-equivalent tests that improve upon the efficiency of drug design and reduce the dependence on animal use.
Our project is focused on NMR metabolomics, a new technology that can accurately identify changes in cardiomyocyte energy metabolism in response to drug treatment. The project will use CRISPR/Cas9 to genetically modify hIPSC-derived cardiomyocytes by introducing a mutation in the cardiac troponin-T gene, which encodes a protein required for cardiac cells to function properly. The troponin-T mutation is known to elevate the risk of suffering from a drug-induced cardiotoxic response and will therefore help to determine the biological pathways what cause cardiotoxicity to occur. The mutated hIPSC-cardiomyocytes will then be treated with different cardiotoxic drug compounds and the metabolic changes in response treatment will be monitored by NMR metabolomics and compared to changes in hIPSC-cardiomyocyte function.
The project brings together a multi-disciplinary team of supervisors with expertise in stem cell biology, metabolic biochemistry, and cardiac cell physiology. The project will be hosted by the Institute of Life Course and Medical Sciences and the student affiliated to the MRC-ARUK Centre for Integrated research into Musculoskeletal Ageing (CIMA; a collaboration with Newcastle University and the University of Sheffield), The MRC Centre for Drug Safety Sciences and Liverpool Centre for Cardiovascular Sciences. Training in cardiomyocyte biology will be carried out in the Biosciences Institute, Newcastle University.
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