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Using human induced pluripotent stem cells (hiPSCs) and CRISPR-Cas9 gene editing to develop models of cardiac fibrosis (SMITHU19MED)


Norwich Medical School

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

About the Project

Fibrosis is a prevalent and hard-to-treat condition. Of all deaths in the developed world, 45% are associated with chronic fibro-proliferative disease. Although survival rates from heart failure are improving, 20 million people/year still die because of heart failure worldwide. Cardiac fibrosis disrupts the mechanical and electrical activity of the heart, which can lead to sudden cardiac death. As such, cardiac fibrosis is predictive of hospitalization and of an 18-fold increase in likelihood of death.

The need to tackle fibrosis is now internationally well-recognised. As examples, teams tackling this include the EU consortium, FibroTargets, UK Medicines Discovery Catapult and AstraZeneca. Each recognises the need to develop new, more complex models of fibrosis because too many drugs fail to translate from animals to humans.

By using human induced pluripotent stem cells (hiPSCs) and CRISPR-Cas9 gene editing technology, this PhD project aims to create new human in vitro models of cardiac fibrosis. Gene edited hiPSCs will be differentiated to produce force-generating cardiomyocytes, and secretory active cardiac fibroblasts of the same genetic background. We will investigate the interplay between these cell types, creating models that recapitulate the impact of cardiac fibroblasts (and activated myofibroblasts) on cardiomyocyte function. The role of disease causing mutations will be investigate in such models to gain better insights into these diseases and identify new potential therapeutic targets. Ultimately, these models will aid drug discovery pipelines.

For more information on the supervisor for this project, please go here: https://people.uea.ac.uk/en/persons/j-g-smith
The type of programme: PhD
The start date of the project: Oct 2019
The mode of study: Full-time
Entry requirements: Acceptable first degree in biological sciences subject and minimum entry requirement is 2:1 or a Masters degree.

Funding Notes

This PhD studentship is funded by Norwich Medical School. Funding comprises Home/EU fees and a stipend of £15,009 and £1000 per annum to support research training. Overseas applicants may apply but are required to fund the difference between home/EU and overseas tuition fees (in 2019/20 the difference is £14,373 for Norwich Medical School but fees are subject to an annual increase).

References

(i) 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.

(ii) 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.

(iii) 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.

(iv) Gyongyosi, M., et al. (2017). "Myocardial fibrosis: biomedical research from bench to bedside." Eur J Heart Fail 19(2): 177-191.

(v) Travers, J. G., et al. (2016). "Cardiac Fibrosis: The Fibroblast Awakens." Circ Res 118(6): 1021-1040.
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