Research Description:
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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