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Paul M. Epstein, Ph.D.Associate Professor, Department of Cell Biology
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Degree | Institution | Major |
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Other | COLUMBIA UNIVERSITY | Chemistry |
Ph.D. | Albert Einstein School of Medicine | Molecular Biology |
Awards
Name of Award/Honor | Awarding Organization |
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Principal inventor on US Patent Application No. 20090105281 on “Methods of Treating Inflammation” | |
Principal inventor on US Patent No. 5,885,834 on “Synthesis of Antisense Oligodeoxynucleotide of Phosphodiesterase and Inducement of Apoptosis in Human Lymphoblastoid Cells | |
Fellow of the Rosalie B. Hite Foundation for Cancer Research | |
NIH Predoctoral Trainee | |
Scholarship for Woods Hole Marine Biological Laboratory Physiology Program | |
Dean’s List Columbia College | Columbia College |
New York State Regents Scholarship |
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.
Not accepting lab rotation students at this time
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.
Journal Articles
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PDE8 controls CD4(+) T cell motility through the PDE8A-Raf-1 kinase signaling complex.
Cellular signalling 2017 Aug;4062-72
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Different phosphodiesterases (PDEs) regulate distinct phosphoproteomes during cAMP signaling.
Proceedings of the National Academy of Sciences of the United States of America 2017 Jul;114(30):7741-7743
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Differential Expression and Function of PDE8 and PDE4 in Effector T cells: Implications for PDE8 as a Drug Target in Inflammation.
Frontiers in pharmacology 2016 Jan;7259
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Inhibition of breast cancer cell migration by activation of cAMP signaling.
Breast cancer research and treatment 2015 May;152(1):17-28
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Effect of cAMP signaling on expression of glucocorticoid receptor, Bim and Bad in glucocorticoid-sensitive and resistant leukemic and multiple myeloma cells.
Frontiers in pharmacology 2015 Jan;6230
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Expression of phosphodiesterase 6 (PDE6) in human breast cancer cells.
SpringerPlus 2013 Dec;2680
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Regulatory T-cells and cAMP suppress effector T-cells independently of PKA-CREM/ICER: a potential role for Epac.
The Biochemical journal 2013 Dec;456(3):463-73
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Inhibition of PDE3, PDE4 and PDE7 potentiates glucocorticoid-induced apoptosis and overcomes glucocorticoid resistance in CEM T leukemic cells.
Biochemical pharmacology 2010 Feb;79(3):321-9
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PDE8 regulates rapid Teff cell adhesion and proliferation independent of ICER.
PloS one 2010 Jan;5(8):e12011
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Methods of Treating Inflammation
United States Patent Publication Number US20090105281 2009 Jan;1-45
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Phosphodiesterase 8 (PDE8) regulates chemotaxis of activated lymphocytes.
Biochemical and biophysical research communications 2006 Jun;345(2):713-9
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Zaprinast stimulates extracellular adenosine accumulation in rat pontine slices.
Neuroscience letters 2004 Nov;371(1):12-7
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Elevation of intracellular cAMP evokes activity-dependent release of adenosine in cultured rat forebrain neurons.
The European journal of neuroscience 2004 May;19(10):2669-81
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Expression of cGMP-specific phosphodiesterase 9A mRNA in the rat brain.
The Journal of neuroscience : the official journal of the Society for Neuroscience 2001 Nov;21(22):9068-76
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Structure and promoter activity of the mouse CDC25A gene.
Mammalian genome : official journal of the International Mammalian Genome Society 2000 Dec;11(12):1063-9
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Antisense inhibition of phosphodiesterase expression.
Methods (San Diego, Calif.) 1998 Jan;14(1):21-33
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Expression and regulation of mRNA for distinct isoforms of cAMP-specific PDE-4 in mitogen-stimulated and leukemic human lymphocytes.
Cell biochemistry and biophysics 1998 Jan;28(2-3):135-60
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Inhibition of calmodulin-dependent phosphodiesterase induces apoptosis in human leukemic cells.
Proceedings of the National Academy of Sciences of the United States of America 1996 Oct;93(20):11236-41
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Inhibition of calmodulin-dependent phosphodsterase induces apoptosis in human leukemic cells
Biochemical Society Transactions 1996 Jan;24(4):
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A novel cyclic GMP stimulated phosphodiesterase from rat brain.
Biochemical and biophysical research communications 1994 Dec;205(3):1850-8
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Relationship between phosphorylation and cytochrome P450 destruction.
Archives of biochemistry and biophysics 1990 Dec;283(2):285-92
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Calmodulin dependence of transferrin receptor recycling in rat reticulocytes.
The Biochemical journal 1990 Feb;266(1):261-72
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Echothiophate and cogeners decrease the voltage dependence of end-plate current decay in frog skeletal muscle.
The Journal of pharmacology and experimental therapeutics 1989 Dec;251(3):810-6
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Phosphorylation of cytochrome P450: regulation by cytochrome b5.
Archives of biochemistry and biophysics 1989 Jun;271(2):424-32
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Inverse relationship between cytochrome P-450 phosphorylation and complexation with cytochrome b5.
Archives of biochemistry and biophysics 1987 Dec;259(2):441-8
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Ontogenetic changes in adenylate cyclase, cyclic AMP phosphodiesterase and calmodulin in chick ventricular myocardium.
The Biochemical journal 1987 Apr;243(2):525-31
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Photoaffinity labelling of a 33-35,000 dalton protein in cardiac, skeletal and smooth muscle membranes using a new 125I-labelled 1,4-dihydropyridine calcium channel antagonist.
Life sciences 1986 Dec;39(25):2401-9
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Catalytic and kinetic properties of purified high-affinity cyclic AMP phosphodiesterase from dog kidney.
Archives of biochemistry and biophysics 1982 Oct;218(1):119-33
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Interaction of calcium antagonists with cyclic AMP phosphodiesterases and calmodulin.
Biochemical and biophysical research communications 1982 Apr;105(3):1142-9
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Local anesthetics, mepacrine, and propranolol are antagonists of calmodulin.
Proceedings of the National Academy of Sciences of the United States of America 1981 Feb;78(2):795-9
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Muscarinic antagonism of the effects of phosphodiesterase inhibitor (methylisobutylxanthine) in embryonic chick ventricle.
The Journal of pharmacology and experimental therapeutics 1980 Nov;215(2):348-56
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Chemotherapy of advanced ovarian cancer.
Connecticut medicine 1974 Jan;38(1):1-3
Other
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Identification and characterization of a Ca2+-calmodulin-sensitive cyclic nucleotide phosphodiesterase in a human lymphoblastoid cell line.
The Biochemical journal 1987 Apr;243(2):533-9
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Muscarinic receptors in rat superior cervical ganglia
Annals of the New York Academy of Sciences 1986 Jan;VOL. 46394-95
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Displacement of [3H]phencyclidine binding to Torpedo electric organ membrane by calcium channel antagonists.
Biochemical pharmacology 1984 Dec;33(24):4087-9
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Comparative aspects of nicotinic receptor blockade by ketamine, ditran, and lobeline
Federation Proceedings 1982 Jan;41(4):
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Irreversible inhibition of [<sup>125</sup>I]-α-bungarotoxin and [<sup>3</sup>H] phencyclidine binding to torpedo postsynaptic membranes by trifluoperazine
Federation Proceedings 1982 Jan;41(4):
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Antagonism by acetylcholine of the positive inotropic and cyclic AMP-elevating effects of 1-methyl-3-isobutylxanthine in embryonic chick ventricle
Federation Proceedings 1981 Jan;40(3 I):
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Antagonism of calmodulin by local anesthetics, mepacrine, and propranolol.
Annals of the New York Academy of Sciences 1980 Jan;356441-2
Reviews
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Cyclic nucleotide phosphodiesterases as targets for treatment of haematological malignancies.
The Biochemical journal 2006 Jan;393(Pt 1):21-41
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The Role of PDE8 in T Cell Recruitment and Function in Inflammation
Frontiers in Cell and Developmental Biology; Manuscript reviewed and accepted pending minor revisions