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Projects:
The overall theme of the research projects carried out in our
laboratory is understanding the properties of cAMP signaling.
A major focus is on cyclic nucleotide phosphodiesterases, the
enzymes that degrade and inactivate cAMP. Our hypothesis is that PDE
regulation determines the properties of the cAMP signal. Of the 11
families of PDE's and the 25 genes present in the human genome, we have focused mostly on the PDE4 enzymes specific for cAMP. We have
generated mice lines for three PDE4 genes and we use these models to
understand how cAMP signaling is affected by these enzymes.
The major ongoing projects in the lab are the following:
1. Structure function of PDE4's
We are investigating the properties of a regulatory
domain present at the amino terminus of PDE4. This domain is conserved from C. Elegans to humans. We believe
that this domain serves at least two functions: it serves as the
dimerization domain of the PDE4 and phosphorylation
at the amino terminus controls the interaction of this domain with the
catalytic domain. The phosphorylation by PKA serves as a negative
feedback loop in the cell to regulate cAMP signaling.
2. The role of PDE4 in signaling in inflammatory cells.
3. cAMP regulation of meiosis
cAMP plays a critical role in meiosis in amphibians
and mammalian oocytes. Cyclic AMP signaling maintains the meiotic
arrest by maintaining and inactivating the cdc2/cyclin B complex. The lab is
focusing on identifying the different steps in this pathway. We have
discovered that PDE3 plays a critical role in maintaining the meiotic
arrest in vitro and in vivo. We are now using both mouse and frog
oocyte models to extend these studies.
4. cAMP regulation of spermatozoon function.
Cyclic AMP plays a critical role in the
control of flagellar motility. We have defined several properties of a
unique adenylyl cyclase expressed in the spermatozoon and have shown that
this cyclase is indispensable for motility and fertilization. We are
further investigating the signaling pathways that converge on these
enzymes.
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