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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

        BS University of California, San Diego 1979
        Ph.D University of Pittsburgh, PA 1984
        Postdoctoral Fellow
        Molecular Neurobiology Laboratory
        The Salk Institute, San Diego, CA
        1984-1988
        Assistant Professor
        Department of Biochemistry
        Dartmouth Medical School, Hanover, NH
        1989-1992
        Assistant Professor
        Institute of Biotechnology
        University of Texas Health Science Center at San Antonio, TX
        1992-1997
        Associate Professor
        Department of Molecular Medicine
        University of Texas Health Science Center at San Antonio, TX
        1997-2000

        Associate Professor
        Department of Psychiatry
        University of Massachusetts Medical School, Worcester

        Professor
        Department of Psychiatry
        University of Massachusetts Medical School, Worcester

        2000-2014

         

        2014-present

         

         

         

        Regulation of Nicotinic Receptor Gene Expression in Addiction and Lung Cancer

        Dr. Paul Gardner

        The highly addictive properties of nicotine have been appreciated for a number of years.  Nicotine addiction begins with the interaction of the drug, usually obtained from tobacco, with nicotinic acetylcholine receptors (nAChR) in the brain; the neurotransmitter acetylcholine being the endogenous ligand for the receptors.  The interaction of nicotine with nAChRs occurs within the dopamine reward pathway and leads to increased dopamine release within the brain.  The nicotine-mediated release of dopamine is critical for the onset and maintenance of dependence.  The health consequences of nicotine addiction are staggering.  Tobacco use is the primary etiological factor for the majority of lung cancer cases, the leading cause of cancer-related deaths in the world.  This is reflected in the fact that tobacco contains approximately 55 carcinogens and that nicotine contained in tobacco is one of the most addictive drugs known.  The research in my laboratory is aimed at elucidating the molecular mechanisms controlling expression of the genes encoding nAChRs under both normal and pathological conditions.  Working in close collaboration with the laboratory of Andrew R. Tapper (www.umassmed.edu/bnri/faculty/Tapper.cfm), we use a multidisciplinary approach to address questions related to cholinergic signaling through nAChRs in the brain and the lungs.  This approach is a powerful combination of molecular, biophysical and behavioral analyses allowing us to pursue important issues that span the spectrum ranging from individual genes to whole organisms.

        Nicotinic Acetylcholine Receptor Expression in the Nervous System

        Nicotinic receptors are pentameric ion channels expressed in a variety of cell types.  Neuronal nAChRs are encoded by a family of genes, a2-a10 and b2-b4, and can be assembled as homomeric or heteromeric receptors.  In addition to nicotine addiction, these receptors have been implicated in a variety of brain processes and pathologies including neural development, learning and memory, ageing, anxiety, schizophrenia, Parkinson’s disease and epilepsy.  Thus, understanding how nAChR expression is regulated will have implications for normal development and differentiation as well as for therapies aimed at a variety of neurological pathologies.  Several recent genome-wide association studies have identified a chromosomal locus with genetic variations associated with tobacco use and lung cancer.  Interestingly, this locus maps to a cluster of three nAChR genes, those encoding the a3, a5 and b4 subunits.  My laboratory has studied the transcriptional mechanisms regulating expression of these three genes for a number of years.  Our approach has been to identify transcriptional regulatory elements within the subunit genes and to use these elements as molecular handles to identify and characterize the regulatory factors with which they interact to effect expression of the genes.  We have identified a number of elements and associated factors, some of which are broadly expressed while others have more restricted expression patterns.  More recently, we have turned our attention to post-transcriptional regulation of nAChR expression.  We have carried out a miRNome-wide screen to identify microRNAs (miRNAs) that regulate nAChR expression.  We have identified a limited number of candidate miRNAs that are the focus of current work.  Interestingly, the expression of several of these candidates is regulated by chronic nicotine treatment.  This is likely to be relevant to the molecular mechanisms underlying nicotine dependence.

        Nicotinic Receptors and Nicotine Addiction

        It is clear that nicotine addiction begins with the activation of nAChRs.  However, exactly which specific nAChR subtypes are involved in the addiction process remains to be completely elucidated.  Furthermore, it is likely that specific nAChR subtypes mediate distinct dependence-related behaviors (e.g., reward vs. withdrawal).  In collaboration with the Tapper laboratory, we are attempting to identify nAChR subtypes involved in these processes with the goal of identifying potential therapeutic targets for nicotine cessation.

        Nicotinic Receptors and Lung Cancer

        Lung cancer is the leading cause of cancer-related deaths in the world.  To make matters worse, lung cancer has proven refractory to advances in cancer treatment with only 14% of the patient pool surviving longer than 5 years after diagnosis.  In addition to its role in the nervous system, it is now clear that nicotine promotes several cancer-related phenotypes including cell proliferation, transformation, angiogenesis and apoptotic inhibition.  Another goal of our research is to determine the specific nAChR subtypes that mediate these processes in lung cancer.  Using quantitative RT-PCR, we demonstrated differential expression of the various nAChR subunit genes across distinct lung cancer cell lines and patient samples.  Interestingly, many of these genes are overexpressed in small cell lung cancer (SCLC), the most aggressive form of lung cancer and one that is also tightly associated with cigarette smoking.

        In line with our objective, we are studying the molecular mechanisms that govern the expression of nAChR subunit genes in lung cancer.  We have shown that achaete-scute complex homolog 1 (ASCL1), a transcription factor that is overexpressed in SCLC regulates expression of several nAChR subunit genes.  We are pursuing these observations using a variety of techniques to further elucidate the mechanisms by which ASCL1 exerts this regulation.  Very recently, we have shown that signaling via nAChRs containing the a3, a5 and b4 subunits promotes SCLC cell viability, suggesting a key role for the receptors in lung carcinogenesis.  Our long-term goal is to identify novel therapeutic targets for the treatment of SCLC.



        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. 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.
        2. 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
        3. 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
        4. Liu L, Zhao-Shea R, McIntosh JM, Gardner P, Tapper A. Nicotine Persistently Activates Ventral Tegmental Area Dopaminergic Neurons Via Nicotinic Acetylcholine Receptors Containing a4 and a6 subunits. Mol Pharmacol. 2012 Jan 5.
          View in: PubMed
        5. 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
        6. 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
        7. 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
        8. 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
        9. 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
        10. 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
        11. 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
        12. 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
        13. 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
        14. 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
        15. 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
        16. 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
        17. 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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