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Unravelling the molecular mechanisms of integrin and interleukin-1 cross-talks during inflammation following acute brain injury

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

Project Description

Stroke has a major socio-economic impact, causing death or disability to millions, and costing over £6 billion per annum in the UK. Understanding the mechanisms of brain damage after stroke and developing new therapeutic approaches is therefore a social and clinical priority.
A key event during stroke is inflammation, within and outside the brain, which contributes to brain injury and poor outcome, and a key mediator of inflammation is the cytokine interleukin-1 (IL-1). Another key event is the degradation and remodelling of the extracellular matrix (ECM) of the brain, the integrity of which is critical for normal brain function.
Complex inter-relationships between cytokines and ECM can fundamentally modulate cellular behaviour. In peripheral tissues, IL-1 treatment induces up-regulation of fibronectin production, whilst adhesion to fibronectin can lead to IL-1 generation. The major IL-1 signalling receptor, IL-1R1, has been detected within focal adhesions, sites of close contact between cells and ECM, and adhesion to fibronectin induces association of IL-1R1 with heparan sulphate proteoglycan.
We have shown that ECM molecules regulate IL-1 actions in brain cells, but the molecular mechanisms of ECM / IL-1 crosstalk are largely unknown. This project will aim to identify the signalling mechanisms by which ECM molecules regulate IL-1 actions in brain endothelial cells and astrocytes (using cell lines) by mass spectrometry and Western blot, and will assess the effect of these responses on neuronal injury using cell death assays. The ultimate aim will be to translate these findings in vivo using an experimental mouse model of cerebral ischaemia.

Funding Notes

This project has a Band 3 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

1. The acute-phase protein PTX3 is an essential mediator of glial scar formation and resolution of brain edema after ischemic injury. (2014) Rodriguez-Grande B, Swana M, Nguyen L, Englezou P, Maysami S, Allan SM, Rothwell NJ, Garlanda C, Denes A, Pinteaux E. J Cereb Blood Flow Metab. 34, 802-812.

2. Summers L, Kangwantas K, Rodriguez-Grande B, Denes A, Penny J, Kielty C, Pinteaux E. (2013) Brain endothelial cells activation by interleukin-1 is regulated by adhesion to the extracellular matrix after acute brain injury.Mol. Cell. Neurosci. 57, 93-103.

3. Neutrophil cerebrovascular transmigration triggers rapid neurotoxicity through release of proteases associated with de-condensed DNA. (2012) Allen CM, Thornton P, Denes A, McColl BW, Pierozynski A, Monestier M, Pinteaux E, Rothwell NJ, Allan SM. J. Immunol. 189, 381-392.

4. Summers L, Kangwantas K, Nguyen L, Kielty C, Pinteaux E. (2010) Adhesion to the extracellular matrix is required for interleukin-1 beta actions leading to reactive phenotype in rat astrocytes. Mol. Cell. Neurosci. 44, 272-281.

5. Summers L, Kielty C, Pinteaux E. (2009) Adhesion to fibronectin regulates interleukin-1beta expression in microglial cells. Mol. Cell. Neurosci. 41, 148-155.

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