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Faculty
Paul M. Epstein
Associate Professor of Cell Biology
epstein@nso1.uchc.edu
Areas of Interest:
Dr. Epstein's laboratory has been studying cyclic nucleotide
phosphodiesterases (PDE), a large family of isozymic enzymes which
control the cellular levels of two key signal transduction molecules,
cAMP and cGMP, and thereby play a role in controlling a wide variety of
critical cellular functions. Through cloning and sequence analysis, he
is identifying different forms of phosphodiesterase and determining
their expression and subcellular localization during normal development
and in association with pathophysiological disease states. One disease
sate he is concentrating on in particular is leukemia. He has found that
a 63 kDa form of calmodulin-dependent PDE (PDE1B1) is expressed in
leukemia cells but not in normal quiescent human lymphocytes. He cloned
the cDNA for this gene and developed antisense oligonucleotides (ASODNs)
against it. When he disrupts the expression of the gene for PDE1B1 with
these AS ODNs, it triggers apoptosis in leukemic cells without any
effect on normal resting lymphocytes. Hence these studies pioneer the
basis for a possible new therapy for leukemia. Similar studies are now
being undertaken with respect to breast cancer.
Lab Rotation Projects:
Most of the emphasis of the lab at the moment is identifying forms of
PDE as targets for inducing apoptosis of cancer cells. We are also
collaborating with two colleagues in Pharmacology, Drs. Joel Pachter and
Stefan Brocke, to examine a potential role for inhibitors of PDE to
strengthen the blood brain barrier as a means of treating Alzheimer’s
Disease, and to examine a potential role for PDEs in regulating
lymphocyte chemotaxis and transendothelial migration in relation to
treating multiple sclerosis. Students are free to design their own
projects, but possibilities are:
Project 1: We have found that stimulating the cAMP signaling
pathway can overcome the resistance to inducing apoptosis in leukemic
cells from patients that have developed glucocorticoid resistance (see:
Tiwari, S. et al. “Type 4 cAMP Phosphodiesterase (PDE4) Inhibitors
Augment Glucocorticoid-Mediated Apoptosis in B Cell Chronic Lymphocytic
Leukemia (B-CLL) in the Absence of Exogenous Adenylyl Cyclase
Stimulation.” Biochem. Pharmacol. 69:473-483, 2005). The mechanism of
this effect is, however, still unknown. One hypothesis we have is that
cAMP signaling may enhance the expression and/or function of the
BH3-only proapoptotic proteins BAD and BIM, leading to apoptosis of
these resistant cells, and this could be examined as a rotation project.
Project 2: Work from Dr. Pachter’s laboratory has pioneered a
method for culturing primary brain microvascular endothelial cells (BMEC)
in a manner in which the tight junctions of the endothelial cells are
preserved (see: Song, L. and Pachter, J. S. Culture of murine brain
microvascular endothelial cells that maintain expression and
cytoskeletal association of tight junction-associated proteins. In Vitro
Cell Dev Biol Anim, 39: 313-320, 2003). This therefore provides a model
in vitro system in which to examine the effects of agents on the blood
brain barrier. We hypothesize that PDE inhibitors will strengthen the
blood brain barrier by enhancing the expression of expression of the
tight junction-associated proteins, claudin-5, occludin, and zona
occludin-1 (ZO-1), and this could be examined as a rotation project.
Project 3: PDE4 inhibitors have been shown to be effective in
ameliorating the pathogenesis associated with multiple sclerosis (MS) in
EAE animal models of this disease, though it is unclear how they work in
this regard. We hypothesize that PDE4 inhibitors block T lymphocyte
chemotaxis and transendothelial migration through their ability to
induce phosphorylation and inactivation of rhoA resulting in decreased
phosphorylation of myosin light chain, and, with the help of Dr. Brocke
who is a renowned expert in this area, this can be tested in a rotation
project.
Selected Publications:
Dong, H, Osmanova, V, Epstein, P.M. and Brocke, S Phosphodiesterase 8
(PDE8) Regulates Chemotaxis of Activated Lymphocytes. Biochem. Biophys.
Res. Commun. 345:7113-719, 2006.
Lerner, A. and Epstein, P.M. Cyclic Nucleotide Phosphodiesterases as
Targets for Treatment of Haematological Malignancies. Biochem. J.
393:21-41, 2006.
Tiwari, S., Dong, H., Kim, E.J., Weintraub, L., Epstein, P.M. and
Lerner, A. Type 4 cAMP Phosphodiesterase (PDE4) Inhibitors Augment
Glucocorticoid-Mediated Apoptosis in B Cell Chronic Lymphocytic Leukemia
(B-CLL) in the Absence of Exogenous Adenylyl Cyclase Stimulation.
Biochem Pharmacol 69:473-483, 2005.
Lu Y., Li Y., Herin G.A., Aizenman E., Epstein P.M., and Rosenberg,
P.A. Elevation of Intracellular cAMP Evokes Activity-Dependent Release
of Adenosine in Cultured Rat Forebrain Neurons. Eur. J. Neuroscience
19:2669-2681, 2004.
Le, M., Lu, Y., Li, Y., Greene, R.W., Epstein, Paul M., and
Rosenberg, P.A. Zaprinast Stimulates Extracellular Adenosine
Accumulation in Rat Pontine Slices. Neurosci Lett 371:12-17, 2004.
Andreeva, S.G., Dikkes, P., Epstein, P.M. and Rosenberg, P.A.
Expression of cGMP-Specific Phosphodiesterase 9A mRNA in the Rat Brain.
J. Neurosci 21:9068-9076, 2001.
Paskind, M., Johnston, C., Epstein, P.M., Timm, J., Wickramasinghe,
D., Balenger, E., Rodman, L., Magada, D., and Voss, J. 2000. Structure
and Promoter Activity of the Mouse Cdc 25A Gene. Mammalian Genome
11:1063-1069. |
