Dr. Beavo's research group investigates the role of cyclic nucleotide phosphodiesterases (PDEs) in controlling the amplitude and duration of cyclic AMP and cyclic GMP signaling pathways. There are a large number of different isozyme families of PDEs that are differentially regulated by drugs and hormones. Many were first discovered and studied in this laboratory. Included among the agents that regulate PDEs are insulin, glucagon, EDRF and many neurotransmitters. Much of our recent work has been to determine the physiological reasons for the existence of so many isozymes and to understand mechanistically how they function. In order to understand the mechanisms by which different phosphodiesterases are regulated and influence cyclic AMP and cyclic GMP, several different general approaches have been and are being used. The first involves identification, expression or isolation of individual isozyme of phosphodiesterase present in different mammalian tissues. The structural, functional, and kinetic properties of the isolated isozymes are then characterized. A second and related approach has been to develop isozyme specific probes to each phosphodiesterase and utilize them to study localization, function and regulation in crude systems and in intact cells. These include monoclonal antibodies, antisense mRNAs, siRNA, and various drugs. An important new area of research is to develop methods for studying PDE function in specific sub-regions of the cell. Finally, deletion and mutagenesis analysis, analysis of dominant-negative mutants, and reconstitution studies with the expressed products is often used to determine function. More recently we have also initiated gene disruption studies as a mechanism of determining function. Taken together these approaches have yielded at least a partial understanding of the structure, regulation and function of these enzymes in the cell. Particular systems of current interest include the roles of PDEs in inflammation, pulmonary vascular function, cardiac hypertrophy, insulin secretion, and steroidogenesis. We also have a major project on the role of cyclic nucleotides and PDE inhibitors in muscular dystrophy.

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