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Dissecting the interplay between cardiomyocytes and fibroblasts using human stem cell models of disease

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  • Full or part time
    Dr D Pavlovic
    Prof C Denning
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (UK Students Only)
    Funded PhD Project (UK Students Only)

About This PhD Project

Project Description

Applications are invited for a fully-funded PhD Studentship starting in October 2019, under the guidance of Dr Davor Pavlovic (University of Birmingham) and Prof Chris Denning (University of Nottingham). The purpose of this Studentship is to examine the role of cardiac fibroblasts in maintenance of normal electrical function and to investigate their role in development of cardiac arrhythmias.
Project summary: Adult heart is made up of several cell types, with cardiomyocytes, fibroblasts and endothelial cells being the most abundant. Cardiomyocytes and fibroblasts were shown to electrotonically couple1, yet cardiomyocyte-fibroblast functional interactions are poorly characterised and often ignored in experimental approaches. In this project, the student will examine whether fibroblasts contribute to electrical dysfunction using human fibroblast-cardiomyocyte 2D co-culture and our established disease models of clinically relevant sarcomeric mutations.2 The project has three clearly defined aims: 1 Develop and optimise methodology for 2D co-culture3 and high resolution electrophysiological phenotyping4 of human pluripotent stem cell-cardiomyocytes (hPSC-CM) and cardiac fibroblasts, 2. Characterise the effect of cardiomyocyte-fibroblast coupling on electrical function and calcium handling, 3. Utilise Cas9/CRISPR technology to generate/correct hPSC-CM lines expressing common sarcomeric gene mutations and asses their effects on electrophysiological and mitochondrial function in cardiomyocyte-fibroblast co-cultures.
Research Environment and Learning Outcomes: The student will be supervised by Dr Pavlovic (University of Birmingham) and Prof Chris Denning (University of Nottingham). Dr Pavlovic provides expertise in cardiomyocyte culture, cardiomyocyte/fibroblast co-culture and electrophysiological phenotyping.3,4 Prof Denning provides essential expertise in patient-specific hPSC-CM differentiation and correction of mutations.2 The student will have an exceptional opportunity to work in two high profile laboratories and gain valuable expertise in state-of-the-art methodologies. The PhD Student will be fully involved in all aspect of this project, including the differentiation of hPSC-CM, utilisation of Cas9/CRISPR technology to correct pathological mutations,2 and the use of state-of-the-art optical mapping technology for phenotyping of electrical dysfunction in 2D cell cultures. The key outcomes of the PhD Studentship will be to characterise the effects of cardiomyocyte-fibroblast coupling on electrical and mitochondrial activity and calcium handling in hPSC-CM lines expressing clinically relevant sarcomeric mutations and shed light on the role of cardiac fibroblasts in arrhythmia inducibility. All the necessary equipment is already available at the Institute for Cardiovascular Sciences in Birmingham and Department of Stem Cell Biology in Nottingham.
Person Specification: Applicants should have a sound knowledge in one or more areas including, cardiac electrophysiology, molecular biology, cardiac cellular biology and ideally a background in working with pluripotent stem cells. They should have a commitment to research in stem cell differentiation and cardiac biology and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject. Applicants also need to be able to work as part of a multidisciplinary research team according to Good Clinical Practice (GCP) standards.
For further details about the Studentship please contact Dr Davor Pavlovic ([Email Address Removed]). Please use the links below for further information about the MRC Impact Doctoral Training Programme and the work by Dr Pavlovic (University of Birmingham) and Prof Chris Denning (University of Nottingham).

https://more.bham.ac.uk/mrc-impact/

https://www.birmingham.ac.uk/staff/profiles/cardiovascular-sciences/pavlovic-davor.aspx

https://www.birmingham.ac.uk/research/activity/cardiovascular-sciences/research/heart-failure-arrhythmias/index.aspx

https://www.nottingham.ac.uk/medicine/people/chris.denning

https://www.nottingham.ac.uk/news/expertiseguide/medicine/professor-chris-denning.aspx

References

1. Kohl, P. and Gourdie R.G. Fibroblast-myocyte electrotonic coupling: does it occur in native cardiac tissue? J Mol Cell Cardiol 70, 37-46 (2014).
2. Mosqueira, D. et al. 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 (2018).
3. Ackers-Johnson, M. et al. A Simplified, Langendorff-Free Method for Concomitant Isolation of Viable Cardiac Myocytes and Nonmyocytes From the Adult Mouse Heart. Circ Res 119, 909-920 (2016).
4. Wen, Q. et al. Transverse cardiac slicing and optical imaging for analysis of transmural gradients in membrane potential and Ca(2+) transients in murine heart. J Physiol 596, 3951-3965 (2018).



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