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

炎症消退是指免疫系统的细胞停止产生促炎因子，并返回到静止状态的过程。这不仅需要停止促炎基因的转录，还需要破坏先前存在的促炎mRNAs--否则这些先前存在的mRNAs将继续被翻译，炎症将持续下去。对促炎基因稳定性的动态调节对于正确把握炎症反应的起始和消退阶段是至关重要的，而慢性炎症性疾病的特征是消退阶段的缺陷。丝裂原活化蛋白激酶(MAPK)p38通路在mRNA稳定性的动态调节中起着关键作用，通过调节一种名为Tristetraprolin(TTP)的选择性mRNA破坏蛋白的表达和活性，控制炎症基因表达的开启和关闭。在这个博士项目中，我们将使用实验方法和数学建模相结合的方法来了解MAPK p38如何通过TTP调节炎症基因的表达。最终目标是确定治疗炎症性疾病的新方法。

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.