Understanding how T cells integrate alternative signal combinations to determine immune response strength and functionality is of critical importance for rational design of immunomodulatory therapies. The PIM kinase family have been identified as important regulators of cell division, survival and protein synthesis independent of, but in parallel to the key signalling molecule mTOR. I propose to use cutting-edge quantitative proteomic technology to identify substrates and downstream protein networks regulated by PIM kinase in activated T cells. I will investigate where these downstream targets qualitatively diverge from, or quantitatively interact with, the mTOR signalling pathway (Objective 1 and 2). Using advanced cell culture and mathematical modelling I will quantify how this co-ordinated activity regulates T cell division, survival and differentiation outcomes (Objective 3). This comprehensive exploration of PIM kinase and mTOR signalling pathway integration will provide important fundamental insight into how these signals combine to regulate T cell fate and may be manipulated in the context of immunotherapy or cancer.
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