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  Modulation of the Hippo signalling pathway to enhance cardiac regenerative capacity


   Faculty of Biology, Medicine and Health

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  Dr D Oceandy, Prof Elizabeth Cartwright  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Common heart diseases such as heart failure (HF) and coronary heart disease (CHD) are characterized by cardiomyocyte loss due to necrosis and apoptosis. Whilst it was widely believed that the adult cardiomyocytes are unable to proliferate, recent evidence suggests that these cells have some degree of regenerative capacity.

However, it is clear that the level of myocyte regenerative capacity in adult human heart is insufficient to compensate for the cell loss due to HF or CHD.

One of the main regulators of cardiomyocyte proliferation is the Hippo signalling pathway. Upregulation of YAP activity, the major downstream effector of the Hippo pathway, increases the regenerative capacity of cardiomyocytes as well as cell survival. Through a genetic screen and subsequent analysis in cultured cardiomyocytes we have identified novel genes and microRNAs as possible novel modulators of Hippo-YAP signalling axis.

Based on this pilot data this project will further explore the role of these novel Hippo regulators in modulating cardiomyocyte proliferation and regeneration. We will perform genetic overexpression and gene silencing experiments in primary cardiomyocytes using adenoviral gene delivery system. Cardiomyocyte proliferation rate, apoptosis and cell survival will be determined in basal condition and following pathological stimulation such as hypoxia or treatment with hypertrophic agonist (phenylephrine). In vivo studies using mouse model of myocardial infarction and pressure overload hypertrophy will also be performed. We will overexpress genes and/or microRNAs by using the cardiotrophic adeno-associated virus 9 (AAV9) as delivery vector or using direct intramyocardial injection of mRNA/microRNAs.

This study will provide evidence as to whether genetic modification of a key signalling pathway in cell regeneration (i.e. the Hippo pathway) will enhance the regenerative capacity and cell survival of cardiomyocytes. It will also provide a unique combination of training in molecular biology and in vivo animal physiology for the student.

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with previous laboratory experience are particularly encouraged to apply.

How To Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/”

Biological Sciences (4) Medicine (26)

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/

References

Triastuti E, Nugroho AB, Zi M, Prehar S, Kohar YS, Bui TA, Stafford N, Cartwright EJ, Abraham S, Oceandy D. Pharmacological Inhibition of Hippo Pathway using XMU-MP-1 Protects The Heart Against Adverse Effects during Pressure Overload. Br J Pharmacol. 2019 Oct;176(20):3956-3971.
Stafford N, Zi M, Baudoin F, Mohamed TMA, Prehar S, De Giorgio D, Cartwright EJ, Latini R, Neyses L, Oceandy D. PMCA4 inhibition does not affect cardiac remodelling following myocardial infarction, but may reduce susceptibility to arrhythmia. Sci Rep. 2021 Jan 15;11(1):1518
Mohamed TM, Abou-Leisa R, Stafford N, Maqsood A, Zi M, Prehar S, Baudoin-Stanley F, Wang X, Neyses L, Cartwright EJ, Oceandy D. The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy. Nature Communications. (2016) 7:11074
Zi M, Maqsood A, Prehar S, Mohamed TM, Abou-Leisa R, Robertson A, Cartwright EJ, Ray SG, Oh S, Lim DS, Neyses L, Oceandy D. The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy. J Biol Chem. (2014) 289(35):24275-88
Oceandy D, Pickard A, Prehar S, Zi M, Mohamed TMA, Stanley PJ, Baudoin FM, Nadif R, Tommasi S, Pfeifer GP, Armesilla AL, Cartwright EJ, Neyses L. The tumour suppressor RASSF1A (Ras-association domain family 1 isoform A) is a regulator of cardiac hypertrophy. Circulation (2009). 120(7):607-16
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