The Maurice lab investigates the role that subcellular compartment-specific hydrolysis of cyclic nucleotide (cAMP and cGMP), by the cyclic nucleotide phosphodiesterases (PDEs), plays in promoting selective cyclic nucleotide-signaling in human arterial endothelial and smooth muscle cells. Since virtually all functions of these cell types are regulated by cyclic nculeotide-signaling systems, our studies may allow identification of novel therapeutic targets for managenment of multiple cardiovascular diseases, including atherosclerosis and restenosis, and in important vascular processes such as vasculogenesis and angiogenesis.
Our laboratory investigates how signal compartmentation allows cAMP to regulate simultaneously myriad cellular events with specificity. Overall, our work shows that Cyclic Nucleotide Phosphodiesterase (PDEs), the sole enzymes that inactivate cAMP by hydrolysis, are critical for specificity in this system. In addition, while our studies demonstrate that PDEs are highly “druggable”, they also identify critical shortcoming in current targeting approaches. Specifically, although humans can generate >100 unique PDE variants, and PDEs are known to operate within unique cAMP signaling compartments in cells, current therapeutic strategies have failed to capitalize on their highly compartmented actions. Indeed, most approaches focus on findings agents that inhibit selected PDE activities by catalytic site inhibition without considering the hyper-localized nature of their actions (review Maurice et al., Nature Reviews, Drug Discovery, 13:290, 2014)1. The research elaborated here is a comprehensive plan to identify strategies that will allow inhibition of PDEs in their “natural environment” (i.e. in compartments) and to begin to translate these strategies into approaches to limit the mal-adaptive consequences of atherosclerosis and angiogenesis.