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    Paul D Gardner PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentPsychiatry
    AddressUniversity of Massachusetts Medical School
    303 Belmont Street
    Worcester MA 01604
    Phone508-856-4035
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBrudnick Neuropsychiatric Research Institute

        Overview 
        Narrative

        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 then Full Professor, 2000 - present
        Department of Psychiatry, 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.


        Rotation Projects

        Rotation Projects

        Project I

        We carried out a miRNome-wide screen using a heterologous expression system to identify microRNAs that regulate neuronal nicotinic acetylcholine receptor (nAChR) expression.  This rotation project will pursue candidates from the screen to determine whether they regulate endogenous nAChR expression in a variety of neuronal-like cell lines.  The student will learn a number of techniques including mammalian cell culture, western blotting, quantitative RT-PCR and methods to over-express microRNAs and to inhibit microRNA expression.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Ngolab J, Liu L, Zhao-Shea R, Gao G, Gardner PD, Tapper AR. Functional Upregulation of a4* Nicotinic Acetylcholine Receptors in VTA GABAergic Neurons Increases Sensitivity to Nicotine Reward. J Neurosci. 2015 Jun 3; 35(22):8570-8.
          View in: PubMed
        2. Zhao-Shea R, DeGroot SR, Liu L, Vallaster M, Pang X, Su Q, Gao G, Rando OJ, Martin GE, George O, Gardner PD, Tapper AR. Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal. Nat Commun. 2015; 6:6770.
          View in: PubMed
        3. Bharadwaj R, Peter CJ, Jiang Y, Roussos P, Vogel-Ciernia A, Shen EY, Mitchell AC, Mao W, Whittle C, Dincer A, Jakovcevski M, Pothula V, Rasmussen TP, Giakoumaki SG, Bitsios P, Sherif A, Gardner PD, Ernst P, Ghose S, Sklar P, Haroutunian V, Tamminga C, Myers RH, Futai K, Wood MA, Akbarian S. Conserved Higher-Order Chromatin Regulates NMDA Receptor Gene Expression and Cognition. Neuron. 2014 Dec 3; 84(5):997-1008.
          View in: PubMed
        4. Hogan EM, Casserly AP, Scofield MD, Mou Z, Zhao-Shea R, Johnson CW, Tapper AR, Gardner PD. miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family. RNA. 2014 Dec; 20(12):1890-9.
          View in: PubMed
        5. Zhao-Shea R, Liu L, Pang X, Gardner PD, Tapper AR. Activation of GABAergic neurons in the interpeduncular nucleus triggers physical nicotine withdrawal symptoms. Curr Biol. 2013 Dec 2; 23(23):2327-35.
          View in: PubMed
        6. Pang X, Hogan EM, Casserly A, Gao G, Gardner PD, Tapper AR. Dicer expression is essential for adult midbrain dopaminergic neuron maintenance and survival. Mol Cell Neurosci. 2014 Jan; 58:22-8.
          View in: PubMed
        7. Improgo MR, Soll LG, Tapper AR, Gardner PD. Nicotinic acetylcholine receptors mediate lung cancer growth. Front Physiol. 2013; 4:251.
          View in: PubMed
        8. Improgo, M.R., Soll, L.G., Tapper, A.R. and Gardner, P.D. Nicotinic acetylcholine receptors mediate lung cancer growth. Frontiers in Physiology. 2013; 4:1-6.
        9. Bharadwaj R, Jiang Y, Mao W, Jakovcevski M, Dincer A, Krueger W, Garbett K, Whittle C, Tushir JS, Liu J, Sequeira A, Vawter MP, Gardner PD, Casaccia P, Rasmussen T, Bunney WE, Mirnics K, Futai K, Akbarian S. Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia. J Neurosci. 2013 Jul 17; 33(29):11839-51.
          View in: PubMed
        10. Liu L, Hendrickson LM, Guildford MJ, Zhao-Shea R, Gardner PD, Tapper AR. Nicotinic acetylcholine receptors containing the a4 subunit modulate alcohol reward. Biol Psychiatry. 2013 Apr 15; 73(8):738-46.
          View in: PubMed
        11. Liu L, Zhao-Shea R, McIntosh JM, Gardner PD, Tapper AR. Nicotine persistently activates ventral tegmental area dopaminergic neurons via nicotinic acetylcholine receptors containing a4 and a6 subunits. Mol Pharmacol. 2012 Apr; 81(4):541-8.
          View in: PubMed
        12. Improgo MR, Johnson CW, Tapper AR, Gardner PD. Bioluminescence-based high-throughput screen identifies pharmacological agents that target neurotransmitter signaling in small cell lung carcinoma. PLoS One. 2011; 6(9):e24132.
          View in: PubMed
        13. Improgo MR, Tapper AR, Gardner PD. Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer. Biochem Pharmacol. 2011 Oct 15; 82(8):1015-21.
          View in: PubMed
        14. Zhao-Shea R, Liu L, Soll LG, Improgo MR, Meyers EE, McIntosh JM, Grady SR, Marks MJ, Gardner PD, Tapper AR. Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. Neuropsychopharmacology. 2011 Apr; 36(5):1021-32.
          View in: PubMed
        15. Scofield MD, Tapper AR, Gardner PD. A transcriptional regulatory element critical for CHRNB4 promoter activity in vivo. Neuroscience. 2010 Nov 10; 170(4):1056-64.
          View in: PubMed
        16. Hendrickson LM, Zhao-Shea R, Pang X, Gardner PD, Tapper AR. Activation of alpha4* nAChRs is necessary and sufficient for varenicline-induced reduction of alcohol consumption. J Neurosci. 2010 Jul 28; 30(30):10169-76.
          View in: PubMed
        17. Improgo MR, Scofield MD, Tapper AR, Gardner PD. From smoking to lung cancer: the CHRNA5/A3/B4 connection. Oncogene. 2010 Sep 2; 29(35):4874-84.
          View in: PubMed
        18. Improgo MR, Scofield MD, Tapper AR, Gardner PD. The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer. Prog Neurobiol. 2010 Oct; 92(2):212-26.
          View in: PubMed
        19. Improgo MR, Schlichting NA, Cortes RY, Zhao-Shea R, Tapper AR, Gardner PD. ASCL1 regulates the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. Mol Cancer Res. 2010 Feb; 8(2):194-203.
          View in: PubMed
        20. Bruschweiler-Li L, Fuentes Medel YF, Scofield MD, Trang EB, Binke SA, Gardner PD. Temporally- and spatially-regulated transcriptional activity of the nicotinic acetylcholine receptor beta4 subunit gene promoter. Neuroscience. 2010 Mar 31; 166(3):864-77.
          View in: PubMed
        21. Zhao-Shea R, Cohen BN, Just H, McClure-Begley T, Whiteaker P, Grady SR, Salminen O, Gardner PD, Lester HA, Tapper AR. Dopamine D2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive {alpha}4 nicotinic receptors via a cholinergic-dependent mechanism. FASEB J. 2010 Jan; 24(1):49-57.
          View in: PubMed
        22. Mou Z, Tapper AR, Gardner PD. The armadillo repeat-containing protein, ARMCX3, physically and functionally interacts with the developmental regulatory factor Sox10. J Biol Chem. 2009 May 15; 284(20):13629-40.
          View in: PubMed
        23. Scofield MD, Br├╝schweiler-Li L, Mou Z, Gardner PD. Transcription factor assembly on the nicotinic receptor beta4 subunit gene promoter. Neuroreport. 2008 Apr 16; 19(6):687-90.
          View in: PubMed
        24. Medel YF, Gardner PD. Transcriptional repression by a conserved intronic sequence in the nicotinic receptor alpha3 subunit gene. J Biol Chem. 2007 Jun 29; 282(26):19062-70.
          View in: PubMed
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