The goal of this project is to understand the molecular mechanisms for cAMP inhibition of lymphocyte proliferation and immune functions. Specifically, we want to understand the molecular interactions and spatio-temporal regulation of the newly mapped PKA- type I-Csk inhibitory pathway regulating Src kinase signalling, which is assembled in lipid rafts where the proximal signalling events in T cell activation take place. We wish to disrupt the PKA type I Csk signalling pathway in lymphoid cells and to study the impact on immunodeficiencies relating to cancer and viral disease.
Furthermore, we have discovered a mechanism whereby the T cell following a CD28 stimulus releases cAMP inhibition of proliferation and permits mitogenic stimulation of T cells through recruitment of a PDE/beta arrestin complex. Targets for these strategies are putative therapeutic approaches to treatment of immunodeficiencies. By elimination of PKA type I effects in patient immune cells, the dysfunction can be reversed and this may po tentially be a useful adjuvant therapy.