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Interleukin 1 signalling the heart

  • 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 associated with high levels of morbidity and mortality, and is an increasing health problem worldwide. One cause is myocardial infarction (MI; “heart attack”) in which coronary arteries become blocked preventing oxygenation of the heart. This results in death of contractile cardiomyocytes and an inflammatory response that may increase cardiac damage. Proinflammatory cytokines including interleukin 1 (IL1) are involved, and clinical trials are in progress to determine if inhibiting IL1 activity at the level of receptor binding is beneficial for MI patients. However, some effects of IL1 on cardiomyocytes are beneficial and a better strategy may be to modulate the response downstream of the receptor.

Previously, we have studied some of the intracellular signalling pathways activated by IL1 in the heart, focusing on the mitogen-activated protein kinases (MAPKs) including ERK1/2, JNKs and p38-MAPKs (Clerk et al. J Mol Cell Cardiol. 1999; 31:2087-2099), and we have examined the effects of IL1 on gene expression (Barrett et al. Cytokine 2013 61:340-344; Yndestad et al. Int J Biochem Cell Biol. 2010; 42:263-272). Recent work has focused on signalling through p38-MAPK to inhibit RIPK1 and prevent necroptosis (manuscript in preparation).

The aim of this project is to delineate in full the IL1 signalling pathway in cardiomyocytes and the heart. Training will be provided in key experimental models used for cardiac research (e.g. ex vivo heart perfusions, primary cardiomyocytes). 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. 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. It is anticipated that the data will enable identification of therapeutic targets to reduce the detrimental effects of IL1 in the heart following a heart attack.
"

Funding Notes

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

References

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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