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Academic Background

B.S.  University of California, San Diego, 1979
Ph.D.  University of Pittsburgh, 1984

Postdoctoral Fellow 1985 - 1989

Molecular Neurobiology Laboratory
The Salk Institute for Biological Studies

Academic Appointments

Assistant Professor, 1989 - 1992
Department of Biochemistry, Dartmouth Medical School
Assistant then Associate Professor, 1992 - 2000
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio
Associate Professor then Professor, 2000 - 2017
Department of Psychiatry, University of Massachusetts Medical School
Professor, 2018 - present
Department of Neurobiology, University of Massachusetts Medical School

Molecular Mechanisms Regulating Synaptic Plasticity in Nicotine Addiction

Tobacco use causes approximately five million deaths worldwide annually and is the leading cause of preventable mortality in the world.  Nicotine is a highly addictive component of tobacco that binds to and activates a family of ligand-gated ion channels, nicotinic acetylcholine receptors (nAChRs) that are normally activated by the endogenous neurotransmitter, acetylcholine.  Activation of the receptors in the dopaminergic (DAergic) mesocorticolimbic reward pathway is thought to underlie the initiation of addiction whereas signaling through nAChRs in a ventral tegmental area-interpeduncular nucleus-medial habenula pathway that feeds into the reward pathway is thought to play a key role in eliciting nicotine withdrawal symptoms.  One of the challenges in understanding nicotine’s affect on nAChRs arises from the existence of multiple nAChR subtypes, each exhibiting unique electrophysiological properties and varying affinities for nicotine.  Eleven distinct neuronal nAChR subunits have been identified (alpha2-7, alpha9, alpha10 and beta2-4).  Five subunits co-assemble to form receptors with the subunit composition of each channel determining its pharmacological and biophysical properties.  Chronic nicotine exposure alters the expression of nAChR subtypes, which likely contributes to nicotine dependence; however, the underlying mechanisms regulating these changes remain unclear.  A growing body of evidence indicates that nicotine and cigarette smoke alters the expression of small 21-24 nucleotide long regulatory molecules, referred to as microRNAs (miRNAs).  We recently used a multifaceted approach involving bioinformatics, miRNA library screening, site-directed mutagenesis and gene expression analysis, to identify a limited number of miRNAs that functionally interact with the 3-untranslated regions (3′-UTRs) of mammalian neuronal nAChR subunit genes.  In silico analyses revealed specific, evolutionarily conserved sites within the 3′-UTRs through which the miRNAs regulate gene expression.  Mutating these sites disrupted miRNA regulation confirming the in silico predictions.  In addition, the miRNAs that target nAChR 3′-UTRs are expressed in the brain and are regulated by chronic nicotine exposure.  Our current work is focused upon the physiological roles these miRNAs play in regulating nAChR expression in the context of nicotine addiction using a plethora of molecular, biophysical and behavioral analyses.  Our long-term goal is to understand how these miRNAs alter nAChR expression and thereby the functional circuitry underlying addiction.  It is our hope that this work will lead to novel targets for therapeutic intervention for smoking cessation as the very few number of therapies currently available are of limited utility.

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