Mathematical modelling of the function of Tristetraprolin, a master regulator of inflammation

The mRNA destabilising protein tristetraprolin (TTP) is a critical anti-inflammatory protein, which negatively regulates the expression of many inflammatory mediators in many different cell types. Its function is regulated by an on-off switch mediated by protein phosphorylation and dephosphorylation (1, 2). Phosphorylation of TTP under the control of the MAPK p38 signalling pathway leads to loss of TTP function, and increased expression of pro-inflammatory genes. Dephosphorylation of TTP by the phosphatase PP2A increases its activity and switches off the expression of pro-inflammatory genes. The importance of this pathway has been demonstrated using two genetically modified mouse strains. TTP-/- mice spontaneously develop severe inflammation caused by over-expression of several pro-inflammatory factors (3). In contrast, TTPaa/aa mice in which TTP cannot be phosphorylated and inactivated under-express pro-inflammatory factors and are strongly protected against damaging inflammation (1, 2, 4). We propose that modulating TTP activity may be a novel and effective way to treat several chronic inflammatory conditions, which collectively impose huge costs at personal, societal and health economic levels.

The objective of this PhD studentship is to use a combination of experimentation and mathematical modelling to explore the dynamic regulation of inflammatory gene expression by TTP, and discover optimal strategies for therapeutic intervention in this pathway. In an iterative process, mathematical models of TTP regulation will determine experimental design, and experimental data will be used to refine models. The TTP pathway will be experimentally perturbed using pharmacological activators or inhibitors of MAPK p38 and PP2A, as well as cells obtained from genetically modified mice, including TTP-/- , TTPaa/aa and DUSP1-/- (in which MAPK p38 activity is increased and TTP is therefore phosphorylated and inactivated). Initial stages of the project can take advantage of plentiful existing data concerning the impact of TTP on inflammatory gene expression.

The student will work between the groups of Andy Clark, who has published extensively on the function and regulation of TTP, and Sara Jabbari, who has published extensively on mathematical modelling of gene regulatory networks. They will therefore gain a unique training in experimental systems biology.

1 Clark, A.R., Dean, J.L.E., 2016. The control of inflammation via the phosphorylation and dephosphorylation of tristetraprolin: a tale of two phosphatases. Biochem Soc Trans 44, 1321-1337.
2 O’Neil, J.D, Ammit, A.J., Clark, A.R., 2018. MAPK p38 regulates inflammatory gene expression via tristetraprolin: doing good by stealth. Int J Biochem Cell Biol 94, 6-9.
3 Brooks, S.A., Blackshear, P.J., 2013. Tristetraprolin (TTP): Interactions with mRNA and proteins, and current thoughts on mechanisms of action. Biochim Biophys Acta 1829, 666-679.
4 Ross, E.A., Smallie, T., Ding, Q., O’Neil, J.D. et al. 2015. Dominant suppression of inflammation via targeted mutation of the mRNA destabilizing protein tristetraprolin. J Immunol 195, 265-276.