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

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.