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Use of induced pluripotent stem cell derived cardiomyocytes to test the consequences of genetic variants in atrial and ventricular arrhythmias


Project Description

Project background:
Inherited cardiac conditions are caused by genetic mutations in cardiac genes. They are the most common cause of sudden cardiac death in the young through ventricular arrhythmias and also contribute substantially to heart failure, putting a major burden on health care systems. To develop specific therapies, it is necessary to understand the consequences of the genetic mutations at the molecular level. This project will utilise induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) to study inherited heart conditions caused by titin truncation variants (TTNtv) and thereby provide an opportunity to replace animal models, especially mice, to study these genetic diseases. TTNtv are found in up to 25 % of patients suffering from dilated cardiomyopathy, one of the major inherited cardiac conditions. There is an increased burden of ventricular arrhythmias in these patients as well as a link of TTNtv and atrial fibrillation (a form of atrial arrhythmia), indicating that TTNtv can predispose to arrhythmias in both settings.
The main scientific objective of the project is to develop experimental iPSC-CM derived cellular model systems (both 2D and 3D) to study the predisposition to atrial and ventricular arrhythmias caused by mutations in cardiac genes and to carry out experiments to characterise the pathological disturbances. This part of the project will take place in the groups of Dr. K Gehmlich and Prof P Kirchhof at the University of Birmingham. The project will also involve computational modelling aspects, which will be undertaken supported by the group of Prof B Rodriguez at the University of Oxford.
Training aspects:
The student will join an interdisciplinary team of world-class researchers at the University of Birmingham, and work closely with computer scientists at the University of Oxford. The student will receive profound training in genome-engineering, culture of iPSC and iPSC-CM, differentiation into cardiac cell types. Moreover the student will acquire skills in molecular biology, protein biochemistry and microscopy, which are all transferable skills beneficial for any lab based research project. Additionally, the student will learn specialist techniques, such as the generation and characterisation of engineered heart tissue and electrophysiological characterisation of 2D and 3D cultures of iPSC-CM and receive training in computational modelling.
Important aspects of lab work are gaining skills in time management, study design, data analysis and statistical evaluation of data, health and safety training and IT skills. Moreover, the student will gain transferable communication skills, both through oral presentations and written work.
The student will receive a wide range of training in 3R approaches (Replacement, Reduction and Refinement of Animal Work), with the main focus on “replacement” in this project and receive support from the local Midlands NC3R Programme Manager.

Funding Notes

Funded jointly by the National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3R) and the British Heart Foundation (BHF)
Funding includes a tax-free stipend (rates are based on MRC guidelines, View Website, tuition fees at the University of Birmingham and a generous research training support grant (approx. £10,000 per year).

References

[1] U Tayal et al. J Am Coll Cardiol 2017. 69: p. 2466-2468.
[2] G Ahlberg et al. Nat Commun 2018. 9: p. 4316.
[3] I Karakikes et al. Circ Res. 2015. 117: p. 80–88.
[4] L Cyganek et al. JCI Insight 2018. 3.
[5] M Paci et al. Heart Rhythm 2017. 14: p. 1704-1712.
[6] MD Lemoine et al. Sci Rep 2017. 7: p. 5464.

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