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Heart failure and the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Heart failure is a leading cause of morbidity and mortality worldwide. The contractile cells of the heart, cardiomyocytes, possess many protective mechanisms, allowing them to withstand pathophysiological stresses. However, they are terminally-differentiated and do not divide after birth. In response to hypertension, cardiomyocytes undergo hypertrophic growth (i.e. increase in size in the absence of cell division) in order to increase cardiac output. Following a myocardial infarction (heart attack) cells in the ischaemic area die and, to maintain cardiac function, surviving cells hypertrophy. The hypertrophic response can maintain a "compensated" state in the short term, but may degenerate as protective mechanisms fail, leading to heart failure. Increasing cardioprotective mechanisms, whilst inhibiting destructive mechanisms is therefore desirable.

Protein kinase signalling pathways regulate all cellular processes and play a pivotal role in modulating the balance between cell survival and cell death. The ERK1/2 cascade is generally recognised for its effects in promoting cell proliferation and cell survival which is why drugs have been developed to inhibit the pathway for the treatment of cancer. In cardiomyocytes, the pathway is associated with hypertrophy and cell survival, raising the question of the effects of on the heart of drugs targeting the ERK1/2 cascade that are in use clinically. In addition, our data indicate that in some conditions the ERK1/2 signal is potently protective in cardiomyocytes, whilst in other situations the protective/growth signal decays and cardiomyocytes start to die. The difference may be attributed to differential signalling through specific isoforms of the downstream p90 ribosomal S6 kinases (RSKs). Whilst activation of RSK2 is associated with survival, activation of RSK1 potentially causes breakdown of the survival response.

This project will explore the in vivo effects of ERK1/2 cascade inhibitors on the heart and examine the role of RSK isoforms in cardioprotection. We will use transgenic and knockout mouse models, in addition to ex vivo (perfused hearts ) and in vitro (cells in culture) systems. A range of biochemical, cell biology and molecular biology techniques will be used (e.g. quantitative PCR, western blotting, primary cell culture, immunofluorescence microscopy, protein kinase assays etc.). Work experience in a molecular biology laboratory would therefore be useful, but training in all techniques can be provided. Training will be provided specifically for heart research systems (primary cultures, ex vivo heart perfusions, in vivo assessment of heart function). An interest in intracellular signalling and understanding of cell biology/biochemistry is important. The position would suit an individual with a particular interest in biomedical research and would be ideally suited to individuals with an interest in the development of heart failure.

Funding Notes

Minimally, students will require self-funding for University fees and maintenance. Bench fees may be negotiated.


Amirak E, Fuller SJ, Sugden PH, Clerk A. p90 ribosomal S6 kinases (RSKs) play a significant role in early gene regulation in the cardiomyocyte response to endothelin-1 or α-adrenergic receptor agonists. Biochem J. 2013; 450:351-353.

Sugden PH, Markou T, Fuller SJ, Tham EL, Molkentin JD, Paterson HF, Clerk A. Monophosphothreonyl extracellular signal-regulated kinases 1 and 2 (ERK1/2) are formed endogenously in intact cardiac myocytes and are enzymically active. Cell Signal. 2011; 23:468-477.

Marshall AK, Barrett OP, Cullingford TE, Shanmugasundram A, Sugden PH, Clerk A. ERK1/2 signaling dominates over RhoA signaling in regulating early changes in RNA expression induced by endothelin-1 in neonatal rat cardiomyocytes. PLoS One. 2010; 5:e10027.

Cullingford TE, Markou T, Fuller SJ, Giraldo A, Pikkarainen S, Zoumpoulidou G, Kemp TJ, Dennis JL, Game L, Sugden PH, Clerk A. Temporal regulation of expression of immediate early and second phase transcripts by endothelin-1 in cardiomyocytes. Genome Biol. 2008; 9:R32.

Kennedy RA, Kemp TJ, Sugden PH, Clerk A. Using U0126 to dissect the role of the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade in the regulation of gene expression by endothelin-1 in cardiac myocytes. J Mol Cell Cardiol. 2006; 41:236-247.

Clerk A, Aggeli IK, Stathopoulou K, Sugden PH. Peptide growth factors signal differentially through protein kinase C to extracellular signal-regulated kinases in neonatal cardiomyocytes. Cell Signal. 2006; 18:225-235.

Valks DM, Cook SA, Pham FH, Morrison PR, Clerk A, Sugden PH. Phenylephrine promotes phosphorylation of Bad in cardiac myocytes through the extracellular signal-regulated kinases 1/2 and protein kinase A. J Mol Cell Cardiol. 2002; 34:749-763.

Clerk A, Michael A, Sugden PH. Stimulation of the p38 mitogen-activated protein kinase pathway in neonatal rat ventricular myocytes by the G protein-coupled receptor agonists, endothelin-1 and phenylephrine. A role in cardiac myocyte hypertrophy? J Cell Biol. 1998; 142:523-535.

Clerk A, Bogoyevitch MA, Andersson MB, Sugden PH. Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine, and subsequent stimulation of p42- and p44-mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts. J Biol Chem. 1994; 269:32848-32857.

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