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    Paul R Dobner PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMicrobiology and Physiological Systems
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-2410
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMolecular Genetics and Microbiology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Overview 
        Narrative

        Academic Background

        BA., SUNY at Buffalo, 1975
        PhD, Columbia University, 1981

        Regulation of Neuroendocrine Gene Expression

        Photo: Paul R. DobnerThe overall goal of this laboratory is to understand the mechanismscontrolling gene expression in the nervous system. Neurons share manycommon functions but differ in two major ways. First, each neuron makes aunique set of connections with the other neurons and target tissues. Second, different sets of neurons express distinct combinations ofclassical neurotransmitters, neuropeptide modulators, and receptors. Thegenes encoding different neurotransmitter systems, therefore provideimportant models for understanding differential gene expression in thenervous system. We first cloned cDNAs and genomic sequences encoding tworelated neuropeptides, neurotensin and neuromedin N, and we are currentlyusing this gene to understand the regulatory pathways that set the complexpattern of expression of the gene throughout the limbic regions of thecentral nervous system. Several lines of evidence suggest that multipleenvironmental factors including estrogen, dopamine, and glucocorticoidsare involved in region-specific expression of the gene. Experiments inPC12 cells, where the gene is regulated synergistically by multipleenvironmental factors, have implicated a highly conserved 200 bp region of5' flanking sequences immediately upstream of the start site oftranscription in the control of neurotensin gene expression. A consensusAP-1 site, the target of the products of the c-fos and c-junproto-oncogenes and their relatives, is a critical control elementrequired for responses to combinations of inducers. Current studies areaimed at understanding the role AP-1 plays in controlling neurotensin geneexpression. Recently, co-transfection experiments in PC12 cells haveprovided evidence that c-Jun is a critical positive transcriptionalactivator of neurotensin gene expression. To directly assess theregulatory role of c-Jun in the nervous system, antisense oligonucleotideswill be used to inhibit c-Jun synthesis and to examine potential effectson the regulation of the gene in response to neuroleptic drugs. Transgenic mouse models will also be used to assess the importance of theAP-1 site for the generation of the complex pattern of expression observedin the adult rat central nervous system. These studies coupled withmutational analysis of a 50 bp region of 5' flanking sequence that isnearly identical in rat and human should allow us to delineate thesequence elements responsible for pattern generation in the centralnervous system.



        Rotation Projects

        Rotation Projects

        The first project involves investigating changes in reponses to the psychostimulant drug amphetamine. Our preliminary evidence indicates that NT knockout mice display region-specific defects in neuronal activation following amphetamine administration. These studies will be extended to investigate amphetamine induction of c-Fos and to compare the ability of amphetamine to stimulate locomotor activity and other behaviors in NT knockout and wild type mice. The student will become familiar with genotype analysis, animal experiments, fixation protocols and immunocytochemistry.

        Another possible project concerns the role of neurotensin in appetite control. We have obtained preliminary evidence that NT-deficient mice gain weight abnormally when fed a high carbohydrate diet, but not when fed a high fat diet. This project will involve an investigation of the effects of the fat cell hormone leptin on feeding behavior in NT knockout mice compared to wild type controls. The effects of leptin on NT gene expression in the hypothalamus will also be investigated using in situ hybridization. The student will become familiar with animal experiments, in situ hybridization procedures, and fixation protocols.



        Bibliographic 
        selected publications
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        1. Carraway RE, Dobner PR. Zinc pyrithione induces ERK- and PKC-dependent necrosis distinct from TPEN-induced apoptosis in prostate cancer cells. Biochim Biophys Acta. 2012 Feb; 1823(2):544-57.
          View in: PubMed
        2. Hall FS, Centeno M, Perona MT, Adair J, Dobner PR, Uhl GR. Effects of neurotensin gene knockout in mice on the behavioral effects of cocaine. Psychopharmacology (Berl). 2012 Jan; 219(1):35-45.
          View in: PubMed
        3. Wang X, Gulhati P, Li J, Dobner PR, Weiss H, Townsend CM, Evers BM. Characterization of promoter elements regulating the expression of the human neurotensin/neuromedin N gene. J Biol Chem. 2011 Jan 7; 286(1):542-54.
          View in: PubMed
        4. Koon HW, Kim YS, Xu H, Kumar A, Zhao D, Karagiannides I, Dobner PR, Pothoulakis C. Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis. Proc Natl Acad Sci U S A. 2009 May 26; 106(21):8766-71.
          View in: PubMed
        5. Gui X, Guzman G, Dobner PR, Kadkol SS. Increased neurotensin receptor-1 expression during progression of colonic adenocarcinoma. Peptides. 2008 Sep; 29(9):1609-15.
          View in: PubMed
        6. Piliponsky AM, Chen CC, Nishimura T, Metz M, Rios EJ, Dobner PR, Wada E, Wada K, Zacharias S, Mohanasundaram UM, Faix JD, Abrink M, Pejler G, Pearl RG, Tsai M, Galli SJ. Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis. Nat Med. 2008 Apr; 14(4):392-8.
          View in: PubMed
        7. Carraway RE, Hassan S, Dobner PR. Protein kinase C inhibitors alter neurotensin receptor binding and function in prostate cancer PC3 cells. Regul Pept. 2008 Apr 10; 147(1-3):96-109.
          View in: PubMed
        8. Dobner PR. Neurotensin and pain modulation. Peptides. 2006 Oct; 27(10):2405-14.
          View in: PubMed
        9. Donelan J, Boucher W, Papadopoulou N, Lytinas M, Papaliodis D, Dobner P, Theoharides TC. Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc Natl Acad Sci U S A. 2006 May 16; 103(20):7759-64.
          View in: PubMed
        10. Fadel J, Dobner PR, Deutch AY. Amphetamine-elicited striatal Fos expression is attenuated in neurotensin null mutant mice. Neurosci Lett. 2006 Jul 10; 402(1-2):97-101.
          View in: PubMed
        11. Dobner PR. Multitasking with neurotensin in the central nervous system. Cell Mol Life Sci. 2005 Sep; 62(17):1946-63.
          View in: PubMed
        12. Kinkead B, Dobner PR, Egnatashvili V, Murray T, Deitemeyer N, Nemeroff CB. Neurotensin-deficient mice have deficits in prepulse inhibition: restoration by clozapine but not haloperidol, olanzapine, or quetiapine. J Pharmacol Exp Ther. 2005 Oct; 315(1):256-64.
          View in: PubMed
        13. Hassan S, Dobner PR, Carraway RE. Involvement of MAP-kinase, PI3-kinase and EGF-receptor in the stimulatory effect of Neurotensin on DNA synthesis in PC3 cells. Regul Pept. 2004 Aug 15; 120(1-3):155-66.
          View in: PubMed
        14. Gui X, Carraway RE, Dobner PR. Endogenous neurotensin facilitates visceral nociception and is required for stress-induced antinociception in mice and rats. Neuroscience. 2004; 126(4):1023-32.
          View in: PubMed
        15. Dobner PR, Deutch AY, Fadel J. Neurotensin: dual roles in psychostimulant and antipsychotic drug responses. Life Sci. 2003 Jun 27; 73(6):801-11.
          View in: PubMed
        16. Gui X, Dobner PR, Carraway RE. Endogenous neurotensin facilitates enterohepatic bile acid circulation by enhancing intestinal uptake in rats. Am J Physiol Gastrointest Liver Physiol. 2001 Dec; 281(6):G1413-22.
          View in: PubMed
        17. Dobner PR, Fadel J, Deitemeyer N, Carraway RE, Deutch AY. Neurotensin-deficient mice show altered responses to antipsychotic drugs. Proc Natl Acad Sci U S A. 2001 Jul 3; 98(14):8048-53.
          View in: PubMed
        18. Fadel J, Dobner PR, Deutch AY. The neurotensin antagonist SR 48692 attenuates haloperidol-induced striatal Fos expression in the rat. Neurosci Lett. 2001 Apr 27; 303(1):17-20.
          View in: PubMed
        19. Tavares D, Tully K, Dobner PR. Sequences required for induction of neurotensin receptor gene expression during neuronal differentiation of N1E-115 neuroblastoma cells. J Biol Chem. 1999 Oct 15; 274(42):30066-79.
          View in: PubMed
        20. Seethalakshmi L, Mitra SP, Dobner PR, Menon M, Carraway RE. Neurotensin receptor expression in prostate cancer cell line and growth effect of NT at physiological concentrations. Prostate. 1997 May 15; 31(3):183-92.
          View in: PubMed
        21. McCabe LR, Banerjee C, Kundu R, Harrison RJ, Dobner PR, Stein JL, Lian JB, Stein GS. Developmental expression and activities of specific fos and jun proteins are functionally related to osteoblast maturation: role of Fra-2 and Jun D during differentiation. Endocrinology. 1996 Oct; 137(10):4398-408.
          View in: PubMed
        22. Harrison RJ, McNeil GP, Dobner PR. Synergistic activation of neurotensin/neuromedin N gene expression by c-Jun and glucocorticoids: novel effects of Fos family proteins. Mol Endocrinol. 1995 Aug; 9(8):981-93.
          View in: PubMed
        23. Evers BM, Wang X, Zhou Z, Townsend CM, McNeil GP, Dobner PR. Characterization of promoter elements required for cell-specific expression of the neurotensin/neuromedin N gene in a human endocrine cell line. Mol Cell Biol. 1995 Jul; 15(7):3870-81.
          View in: PubMed
        24. Bullock BP, McNeil GP, Dobner PR. Synergistic induction of neurotensin gene transcription in PC12 cells parallels changes in AP-1 activity. Brain Res Mol Brain Res. 1994 Dec; 27(2):232-42.
          View in: PubMed
        25. Muraki K, Mitra SP, Dobner PR, Carraway RE. Enhanced expression of neurotensin/neuromedin N mRNA and products of NT/NMN precursor processing in neonatal rats. Peptides. 1993 Nov-Dec; 14(6):1095-102.
          View in: PubMed
        26. Carraway RE, Bullock BP, Dobner PR. Induction of the neurotensin (NT) gene in PC12 cells gives rise to NT precursor (approximately 88%), NT(3-13)-like peptide (approximately 10%), and NT (approximately 2%). Peptides. 1993 Sep-Oct; 14(5):991-9.
          View in: PubMed
        27. Xing Y, Johnson CV, Dobner PR, Lawrence JB. Higher level organization of individual gene transcription and RNA splicing. Science. 1993 Feb 26; 259(5099):1326-30.
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        28. Bean AJ, Dagerlind A, Hökfelt T, Dobner PR. Cloning of human neurotensin/neuromedin N genomic sequences and expression in the ventral mesencephalon of schizophrenics and age/sex matched controls. Neuroscience. 1992 Sep; 50(2):259-68.
          View in: PubMed
        29. Merchant KM, Dobner PR, Dorsa DM. Differential effects of haloperidol and clozapine on neurotensin gene transcription in rat neostriatum. J Neurosci. 1992 Feb; 12(2):652-63.
          View in: PubMed
        30. Dobner PR, Kislauskis E, Bullock BP. Cooperative regulation of neurotensin/neuromedin N gene expression in PC12 cells involves AP-1 transcription factors. Ann N Y Acad Sci. 1992; 668:17-29.
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        31. Tischler AS, Ruzicka LA, Dobner PR. A protein kinase inhibitor, staurosporine, mimics nerve growth factor induction of neurotensin/neuromedin N gene expression. J Biol Chem. 1991 Jan 15; 266(2):1141-6.
          View in: PubMed
        32. Jayaraman A, Nishimori T, Dobner P, Uhl GR. Cholecystokinin and neurotensin mRNAs are differentially expressed in subnuclei of the ventral tegmental area. J Comp Neurol. 1990 Jun 8; 296(2):291-302.
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        33. Kislauskis E, Dobner PR. Mutually dependent response elements in the cis-regulatory region of the neurotensin/neuromedin N gene integrate environmental stimuli in PC12 cells. Neuron. 1990 May; 4(5):783-95.
          View in: PubMed
        34. Alexander MJ, Dobner PR, Miller MA, Bullock BP, Dorsa DM, Leeman SE. Estrogen induces neurotensin/neuromedin N messenger ribonucleic acid in a preoptic nucleus essential for the preovulatory surge of luteinizing hormone in the rat. Endocrinology. 1989 Oct; 125(4):2111-7.
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        35. Alexander MJ, Miller MA, Dorsa DM, Bullock BP, Melloni RH, Dobner PR, Leeman SE. Distribution of neurotensin/neuromedin N mRNA in rat forebrain: unexpected abundance in hippocampus and subiculum. Proc Natl Acad Sci U S A. 1989 Jul; 86(13):5202-6.
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        36. Dobner PR, Tischler AS, Lee YC, Bloom SR, Donahue SR. Lithium dramatically potentiates neurotensin/neuromedin N gene expression. J Biol Chem. 1988 Oct 5; 263(28):13983-6.
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        37. Kislauskis E, Bullock B, McNeil S, Dobner PR. The rat gene encoding neurotensin and neuromedin N. Structure, tissue-specific expression, and evolution of exon sequences. J Biol Chem. 1988 Apr 5; 263(10):4963-8.
          View in: PubMed
        38. Dobner PR, Barber DL, Villa-Komaroff L, McKiernan C. Cloning and sequence analysis of cDNA for the canine neurotensin/neuromedin N precursor. Proc Natl Acad Sci U S A. 1987 May; 84(10):3516-20.
          View in: PubMed
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