|
|
|
 |
Genetic and microarray analysis of endogenous opioid systems; insulin-like growth factor systems in development and cancer; post-translational processing enzymesThe Pintar laboratory has used mammalian molecular genetic approaches to produce 16 lines of mice containing null alleles for genes involved in growth as well as nervous system development and function. Current work involves both the study of these mutant strains using multiple analytic levels as well as producing conditional knock-outs for several genes. Perhaps most notably. the lab has produced knock-outs of the entire opioid system and is now studying the consequences of these mutations on pain perception and anxiety as well as on drug-induced tolerance and dependence. Since specific pathways mediating these processes are interrupted in these mutants. current study involves pharmacological and biochemical approaches to determine the importance of specific second message pathways and opioid receptor dimerization on opioid receptor functions. Gene array studies are also underway to identify the molecular consequences of mutation in our mice. These studies of opioid receptor function are complemented by molecular study of how endogenous ligands for these receptors are produced. which requires the action of multiple enzymes and co-factors. Again mouse models in which these processing enzymes are mutated is a major thrust in this research. Finally. we have also produced targeted mutations of genes in the insulin-like growth factor (IGF) family. Disrupted genes alter processes as divergent as growth and cell death and may also contribute to tumorigenesis. Understanding these phenotypes. as well as the consequences of combinatorial disruption of these IGF system genes. constitutes the third current research avenue in the laboratory. Selected PublicationsWen T, Peng B, Pintar JE. (2009) The MOR-1 opioid receptor regulates glucose homeostasis by modulating insulin secretion. Mol Endocrinol. 23(5):671-8. Miyako K, Cobb LJ, Francis M, Huang A, Peng B, Pintar JE, Ariga H, Cohen P. (2009) PAPA-1 Is a nuclear binding partner of IGFBP-2 and modulates its growth-promoting actions. Mol Endocrinol. 23(2):169-75. Wen T, Ansonoff MA, Pintar JE. (2008) The tail pigmentation pattern of C57BL/6J mice affects nociception/pain quantification in the tail flick test. Eur J Pain. Sep 18. [Epub ahead of print] Burmeister MA, Ansonoff MA, Pintar JE, Kapusta DR. (2008) Nociceptin/orphanin FQ (N/OFQ)-evoked bradycardia, hypotension and diuresis are absent in N/OFQ peptide (NOP) receptor knockout (NOP-/-) mice. J Pharmacol Exp Ther. 326(3):897-904. Weber ML, Farooqui M, Nguyen J, Ansonoff M, Pintar JE, Hebbel RP, Gupta K. (2008) Morphine induces mesangial cell proliferation and glomerulopathy via {kappa}-opioid receptors. Am J Physiol Renal Physiol. 294(6):F1388-97. Ning Y, Schuller AG, Conover CA, Pintar JE. (2008) Insulin-like growth factor (IGF) binding protein-4 is both a positive and negative regulator of IGF activity in vivo. Mol Endocrinol. 22(5):1213-25. Giangreco A, Qin M, Pintar JE, Watt FM. (2008) Epidermal stem cells are retained in vivo throughout skin aging. Aging Cell. 7(2):250-9. Huang P, Chen C, Xu W, Yoon SI, Unterwald EM, Pintar JE, Wang Y, Chong PL, Liu-Chen LY. (2008) Brain region-specific N-glycosylation and lipid rafts association of the rat mu opioid receptor. Biochem Biophys Res Commun. 365(1):82-8. Lofqvist C, Chen J, Connor KM, Smith AC, Aderman CM, Liu N, Pintar JE, Ludwig T, Hellstrom A, Smith LE. (2007) IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth. Proc Natl Acad Sci U S A. 104(25):10589-94. Lee SN, Peng B, Desjardins R, Pintar JE, Day R, Lindberg I. (2007) Strain-specific steroidal control of pituitary function. J Endocrinol. 192(3):515-25. Murali SG, Liu X, Nelson DW, Hull AK, Grahn M, Clayton MK, Pintar JE, Ney DM. (2007) The intestinotrophic effects of exogenous Insulin-Like Growth Factor-I (IGF-I) are not diminished in IGF binding Protein-5 knock-out mice. Am J Physiol Regul Integr Comp Physiol. 292(6):R2144-50. Ning Y, Hoang B, Schuller AG, Cominski TP, Hsu MS, Wood TL, Pintar JE. (2007) Delayed mammary gland involution in mice with mutation of the insulin-like growth factor binding protein 5 gene. Endocrinology. 148(5):2138-47. Hayward MD, Schaich-Borg A, Pintar JE, Low MJ. (2006) Differential involvement of endogenous opioids in sucrose consumption and food reinforcement. Pharmacol Biochem Behav. 85(3):601-11. Della Valle MC, Sleat DE, Sohar I, Wen T, Pintar JE, Jadot M, Lobel P. (2006) Demonstration of lysosomal localization for the mammalian ependymin-related protein using classical approaches combined with a novel density shift method. J Biol Chem. 281(46):35436-45. Pan H, Che FY, Peng B, Steiner DF, Pintar JE, Fricker LD. (2006) The role of prohormone convertase-2 in hypothalamic neuropeptide processing: a quantitative neuropeptidomic study. J Neurochem. 98(6):1763-77. Ning Y. Schuller AG. Bradshaw S. Rotwein P. Ludwig T. Frystyk J. Pintar JE. (2006) Diminished growth and enhanced glucose metabolism in triple knock out mice containing mutations of insulin like-growth factor binding proteins -3. -4. and -5. Mol Endocrinol. 20(9):2173-86. Ansonoff MA. Zhang J. Czyzyk T. Rothman RB. Stewart J. Xu H. Zjawiony J. Siebert DJ. Yan F. Roth BL. Pintar JE. (2006) Antinociceptive and hypothermic effects of salvinorin A are abolished in a novel strain of KOR-1 KO mice. J Pharmacol Exp Ther. 318(2):641-8. Czyzyk TA. Ning Y. Hsu MS. Peng B. Mains RE. Eipper BA. Pintar JE. (2005) Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse. Dev Biol. 287(2):301-13. McLaughlin JP. Land BB. Li S. Pintar JE. Chavkin C. (2006) Prior activation of kappa opioid receptors by U50,488 mimics repeated forced swim stress to potentiate cocaine place preference conditioning. Neuropsychopharmacology. 31(4):787-94. Morgan DJ. Mzhavia N. Peng B. Pan H. Devi LA. Pintar JE. (2005) Embryonic gene expression and pro-protein processing of proSAAS during rodent development. J Neurochem. 93(6):1454-62. Mathon DS. Ramakers GM. Pintar JE. Marinelli M. (2005) Decreased firing frequency of midbrain dopamine neurons in mice lacking mu opioid receptors. Eur J Neurosci. 21(10):2883-6. Chefer VI. Czyzyk T. Bolan EA. Moron J. Pintar JE. Shippenberg TS. (2005) Endogenous kappa-opioid receptor systems regulate mesoaccumbal dopamine dynamics and vulnerability to cocaine. J Neurosci. 25(20):5029-37. Peinado JR. Laurent V. Lee SN. Peng BW. Pintar JE. Steiner DF. Lindberg I. (2005) Strain-dependent influences on the hypothalamo-pituitary-adrenal axis profoundly affect the 7B2 and PC2 null phenotypes. Endocrinology. 146(8):3438-44. Benamar K. McMenamin M. Geller EB. Chung YG. Pintar JE. Adler MW. (2005) Unresponsiveness of mu-opioid receptor knockout mice to lipopolysaccharide-induced fever. Br J Pharmacol. 144(8):1029-31. Kuninger D. Kuzmickas R. Peng B. Pintar JE. Rotwein P. (2004) Gene discovery by microarray: identification of novel genes induced during growth factor-mediated muscle cell survival and differentiation. Genomics. 84(5):876-89. Hayward MD. Hansen ST. Pintar JE. Low MJ. (2004) Operant self-administration of ethanol in C57BL/6 mice lacking beta-endorphin and enkephalin. Pharmacol Biochem Behav. 79(1):171-81. Kas MJ. van den Bos R. Baars AM. Lubbers M. Lesscher HM. Hillebrand JJ. Schuller AG. Pintar JE. Spruijt BM. (2004) Mu-opioid receptor knockout mice show diminished food-anticipatory activity. Eur J Neurosci. 20(6):1624-32. McCarthy LE. Nitsche JF. Pintar JE. Rogers TJ. (2004) The delta-opioid receptor participates in T-cell development by promoting negative selection. J Neuroimmunol. 153(1-2):91-8. Xu M. Petraschka M. McLaughlin JP. Westenbroek RE. Caron MG. Lefkowitz RJ. Czyzyk TA. Pintar JE. Terman GW. Chavkin C. (2004) Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. J Neurosci. 24(19):4576-84. Gomes I. Gupta A. Filipovska J. Szeto HH. Pintar JE. Devi LA. (2004) A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci U S A. 101(14):5135-9. Czyzyk TA. Morgan DJ. Peng B. Zhang J. Karantzas A. Arai M. Pintar JE. (2003) Targeted mutagenesis of processing enzymes and regulators: implications for development and physiology. J Neurosci Res. 74(3):446-55. McLaughlin JP. Myers LC. Zarek PE. Caron MG. Lefkowitz RJ. Czyzyk TA. Pintar JE. Chavkin C. (2004) Prolonged kappa opioid receptor phosphorylation mediated by G-protein receptor kinase underlies sustained analgesic tolerance. J Biol Chem. 279(3):1810-8. Vaughan CW. Bagley EE. Drew GM. Schuller A. Pintar JE. Hack SP. Christie MJ. (2003) Cellular actions of opioids on periaqueductal grey neurons from C57B16/J mice and mutant mice lacking MOR-1. Br J Pharmacol. 139(2):362-7. Neilan CL. King MA. Rossi G. Ansonoff M. Pintar JE. Schiller PW. Pasternak GW. (2003) Differential sensitivities of mouse strains to morphine and [Dmt1]DALDA analgesia. Brain Res. 974(1-2):254-7. Nitsche JF. Pintar JE. (2003) Opioid receptor-induced GTPgamma35S binding during mouse development. Dev Biol. 253(1):99-108. Nitsche JF. Schuller AG. King MA. Zengh M. Pasternak GW. Pintar JE. (2002) Genetic dissociation of opiate tolerance and physical dependence in delta-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci. 22(24):10906-13. Clarke S. Czyzyk T. Ansonoff M. Nitsche JF. Hsu MS. Nilsson L. Larsson K. Borsodi A. Toth G. Hill R. Kitchen I. Pintar JE. (2002) Autoradiography of opioid and ORL1 ligands in opioid receptor triple knockout mice. Eur J Neurosci. 16(9):1705-12. Broom DC. Nitsche JF. Pintar JE. Rice KC. Woods JH. Traynor JR. (2002) Comparison of receptor mechanisms and efficacy requirements for delta-agonist-induced convulsive activity and antinociception in mice. J Pharmacol Exp Ther. 303(2):723-9. Murphy NP. Lam HA. Chen Z. Pintar JE. Maidment NT. (2002) Heroin-induced locomotion and mesolimbic dopamine release is unchanged in mice lacking the ORL.1 receptor gene. Brain Res. 953(1-2):276-80. Hayward MD. Pintar JE. Low MJ. (2002) Selective reward deficit in mice lacking beta-endorphin and enkephalin. J Neurosci. 22(18):8251-8. |
|
