Spatiotemporal Regulation of cAMP Signalling in Health and Disease

Signalling networks involving the signal molecule cAMP and protein kinase A (PKA) are involved in regulation of a multitude of body functions involving most organ systems of the body. An emerging principle is that function of the cAMP signal pathway in th ese settings requires subcellular anchoring of the components of the pathway and that anchored pools of kinase are vital for function. The list of cAMP regulated functions is long and implicates this signal pathway in some of the major health problems inc luding, but not restricted to cardiovascular disease, type II diabetes, obesity, chronic infection and cancer. However, no systematic approach has explored the therapeutic potential in targeting anchored cAMP signal pathways diseases with dysregulated cAM P signalling. Current and on-going work in the group is aimed at understanding the complex pathways of cAMP signalling which involves a number of PKA isozymes, a diversity of phosphodiesterase enzymes (PDEs) that degrade cAMP, and a number of other compon ents such as A kinase anchoring proteins (AKAPs) implicated in localization of enzyme complexes. The number of AKAPs has been estimated to more than 75 of which 50 have been identified to date. Secondly, understanding signalling via localized pools of cAM P, the spatiotemporal resolution which is tuned by PDEs, and how such cAMP gradients target anchored PKA bound to AKAPs is an area of focus. Lastly, understanding of how cAMP signalling networks in the cell cross-talk with and integrate into the complex w eb of signal pathways in the cell is explored. The lab has interest in cAMP immunomodulation with application in immunodeficiencies and anti-tumor immunity as well as hormonally regulated physiological and pathophysiological processes. We will generate mo dels to target cAMP signalling pathways, unravel new genes to be characterized, identify targets, and provide proof of principle experiments vs. human diseases using specific disease models.