The ability of the innate immune system to discriminate between stimuli that pose little danger and those that threaten the host is a key determinant of human health. The concentration of microbial-associated molecules that activates an innate inflammatory response is determined by the activation threshold of key signalling pathways. This is an important mechanism used by innate immune cells to distinguish between threats that should be tolerated and those that require a strong inflammatory response. This project is based on our recent findings that the stability of TPL-2 (MAP3K8), a key activator of the mitogen activated protein kinase (MAPK) pathway, controls the cellular decision to respond to inflammatory stimuli. Our studies so far have identified the nucleus as the key site regulating the stability of TPL-2. This project will investigate the regulation MAPKs in the nucleus during innate immune cell responses; explore novel functions of MAPKs in the nucleus; and investigate the impact of altering MAPK activation on cellular responses to inflammatory stimuli. The findings will provide fundamental insights into the regulation of the cellular response to inflammatory stimuli and contribute to the development of novel strategies for the therapeutic control of inflammation.
Summary aim: This project will investigate regulation and function of MAPKs in the nucleus during innate immune cell activation.
Techniques to be used: CRISPR/Cas9 gene editing, molecular biology (including site directed mutagenesis), chromatin immunoprecipitation, immunoblotting, cell culture, real-time PCR.