Optimising the treatment of inflammation by targeting the phosphorylation of tristetraprolin: a combined experimental and mathematical modelling appro

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Resolution of inflammation refers to a process in which cells of the immune system cease to produce pro-inflammatory factors, and return to a resting state. This requires not only a halt to the transcription of pro-inflammatory genes, but also the destruction of pre-existing pro-inflammatory mRNAs - otherwise those pre-existing mRNAs would continue to be translated and inflammation would be sustained. Dynamic regulation of the stability of pro-inflammatory mRNAs is critical for correct timing of both the initiation and resolution phases of inflammatory responses, and chronic inflammatory diseases are characterised by defects in the resolution phase. The mitogen-activated protein kinase (MAPK) p38 pathway has a key role in this dynamic regulation of mRNA stability, controlling both the on- and off-phases of inflammatory gene expression by regulating the expression and activity of a selective mRNA-destabilising protein called tristetraprolin (TTP). In this PhD project we will use a combination of experimental approaches with mathematical modelling to understand how MAPK p38 regulates programmes of inflammatory gene expression via TTP. The ultimate goal is to identify new methods of treatment of inflammatory diseases.