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Projects
We determined that CXCR4 signaling is
dysregulated in brain tumor cells as compared to
normal counterparts resulting in abnormally prolonged suppression
of cAMP in response
to CXCL12. These low levels of cAMP stimulate brain tumor growth
and appear to
comprise a mechanism of resistance to anti-tumor therapy. Such
sustained suppression of
cAMP suggests that normal counter-regulation of CXCR4 signaling,
known as
desensitization, is not occurring in brain tumor cells.
Desensitization involves the
phosphorylation of ligand-bound CXCR4 by kinases belonging to the
G-protein receptor
kinase (GRK) family and the binding of arrestins. We are currently
examining how
changes in expression and activation of GRKs and changes in CXCR4
phosphorylation
regulate cAMP suppression and CXCL12-induced tumor cell growth in
vitro and in vivo.
CXCR4 activation is essential for normal
cerebellar development. We showed that
CXCL12 works in concert with sonic hedgehog to regulate cerebellar
granule neuron
proliferation. We are currently examining sonic hedgehog
modulation of CXCR4
signaling, especially CXCR4 desensitization and CXCR4-mediated
cAMP suppression.
We demonstrated that phosphodiesterases type 4
is a potent stimulator of brain tumor
growth in vivo and that inhibition of PDE4 has significant
anti-brain tumor growth
effects. We are currently investigating whether PDE4A can
contribute to oncogenesis and
by which mechanism it promotes growth.
In collaboration with Dr. Jeffrey Leonard from
the Department of Neurosurgery we have
established primary intracranial xenografts of human brain tumors.
These in vivo cultures
provide a novel model system in which to study the biology of
human brain tumors.
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SCHOOL OF MEDICINE
