Education

Degree	Institution	Major
BA	COLUMBIA UNIVERSITY	Chemistry
PhD	ALBERT EINSTEIN COLLEGE OF MEDICINE	Molecular Biology

Awards

Name of Award/Honor	Awarding Organization
Principal inventor on US Patent Application No. 20090105281 on “Methods of Treating Inflammation”	United States Patent and Trademark Office
Principal inventor on US Patent No. 5,885,834 on “Synthesis of Antisense Oligodeoxynucleotide of Phosphodiesterase and Inducement of Apoptosis in Human Lymphoblastoid Cells	United States Patent and Trademark Office
Fellow of the Rosalie B. Hite Foundation for Cancer Research	Rosalie B. Hite Foundation
NIH Predoctoral Trainee	NIH
Scholarship for Woods Hole Marine Biological Laboratory Physiology Program	Marine Biological Laboratory
Dean’s List Columbia College	Columbia College
New York State Regents Scholarship	New York State

Name & Description	Category	Role	Type	Scope	Start Year	End Year
Committee on Undergraduate Medical Education (CUME)	Education Committee	Chair	UConn Health	University	2023	2028
Cells	Professional/Scientific Journal	Editorial Board	External	International	2020
UCH Medical School Coaching Program	Advisory Committee	Advisor	UConn Health	University	2016	2020
American Association for Cancer Research	Professional/Scientific Organization	Member	External	National	2007
Biochemical Journal	Editorial Board	Editorial Advisor	External	International	2003
Medical and Dental Student Research Day Committee	Research Committee	Member and Chair	UConn Health	University	1996	2012
Committee on Student Research	Research Committee	Chair	UConn Health	University	1994	2012
NIH Physiological Chemistry Study Section	Study Section	Member	External	National	1989
Director of the Graduate Program in Cell and Molecular Pharmacology	Education Committee	Director	UConn Health	University	1988	1999
Society for Neuroscience	Professional/Scientific Organization	Member	External	National	1983
American Society for Pharmacology and Experimental Therapeutics	Professional/Scientific Organization	Member	External	International	1975
New York Academy of Sciences	Professional/Scientific Organization	Member	External	International	1975
American Association for the Advancement of Science	Professional/Scientific Organization	Member	External	International	1975
Sigma XI	Professional/Scientific Organization	Member	External	International	1975

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

Books

Book Chapters

Other

Reviews

Title or Abstract	Type	Sponsor/Event	Date/Year	Location
PDEs in Vascular and Metabolic Processes	Panel Discussion	Gordon Research Conference on Cyclic Nucleotide Phosphodiesterases	2022	Gordon Research Conference, Les Diablerets Switzerland
Cyclic Nucleotide Phosphodiesterase 8 as a Target to Treat Autoimmune Inflammation	Talk	Gordon Reseach Conference on Cyclic Nucleotide Phosphodiesterases	2022	Gordon Research Conference, Les Diablerets Switzerland
"Phosphodiesterase 8A domains at the site of leucocyte-endothelial cell adhesion in ulcerative colitis submucosa."	Poster	13th Congress of ECCO. Inflammatory Bowel Disease	2019	13th Congress of ECCO, Inflammatory Bowel Disease
Novel Approaches to Overcoming Glucocorticoid Resistance in the Treatment of Lymphoid Leukemias	Poster	Gordon Research Conference	2018	Sunday River Maine
Targeting Phosphodiesterase-8: PDE8 Controls Autoimmune Inflammation by Mechanisms Distinct from PDE4 Inhibition	Talk	Gordon Research Conference	2018	Sunday River Maine
Modulating inflammatory properties of brain derived endothelial cells through PDE8	Poster	MS Society	2016	Rocky Hill Connecticut
Targeting the PDE8A-Raf-1 kinase signaling complex to treat autoimmune inflammation	Poster	MS Society	2016	Rocky Hill Connecticut
Discovering New Medicines with a Novel Drug Target - PDE8	Talk	CURE	2014	UConn Health
Targeting PDE8 to treat inflammation in vivo		Gordon Research Conference	2014	Mt Holyoke MA
The Role of PDE8 in EAE	Poster		2014	Mt Holyoke MA
Inhibition of Breast Cancer Cell Migration by Activation of cAMP Signaling	Talk	Gordon Research Conference	2014	Mt Holyoke MA
Interplay Between Glucocorticoid and cAMP Signaling on Induction of Apoptosis in Leukemia and Multiple Myeloma Cells	Talk	Gordon Research Conference	2010	Waterville Valley NH
Inhibition of Breast Cancer Metastasis by Activation of cAMP Signaling	Talk	Connecticut Breast Health Initiative	2008	New Britain CT
PDE8 as a Potential Target for Inhibition of Lymphocyte Chemotaxis	Talk	Gordon Research Conference	2006	U. of New England Biddeford ME
Interplay Between Glucocorticoid and cAMP Signaling Pathways on Induction of Apoptosis in Leukemic Cells	Talk	Gordon Research Conference	2004	Barga Italy
Exisulind and Its Derivatives Inhibit Jurkat Cell Proliferation by an Apparent Non-cGMP Dependent Mechanism	Poster	Gordon Research Conference	2002	Mt Holyoke MA
PDE as a potential target for inducing apoptosis of breast cancer cells	Talk	Gordon Research Conference	2000	Oxford U. England
Co-Expression of Four Splice Variants of cGMP-Stimulated Phosphodiesterase (PDE2) in Rat Brain	Talk	Gordon Research Conference	1999	Waterville Valley ME
Cloning of the Human PDE1B1 Gene and its Potential as a Therapeutic Target for Treatment of Leukemia	Talk	Gordon Research Conference	1998	New London NH
PDE1 Molecular Biology and Therapeutics	Talk	William Harvey Research Conference	1997	Royal College of Physicians, London England