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A new approach to various diseases based on abnormal metabolism of petering.

Research Project

Project/Area Number 14570133
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionFujita Health University

Principal Investigator

ICHINOSE Chino  Fujita Health University, School of Medicine, Professor, 医学部, 助教授 (10247653)

Co-Investigator(Kenkyū-buntansha) IKEMOTO Kazuhisa  Fujita Health University, School of Medicine, Assistant, 医学部, 助手 (40351019)
SHIRAISHI Hiroaki  Fujita Health University, School of Medicine, Assistant, 医学部, 助手 (80319285)
NOMURA Takahide  Fujita Health University, School of Medicine, Professor, 医学部, 教授 (20156227)
ICHINOSE Hiroshi  Tokyo Institute of Technology, Graduate School of Bioscience and Biotechnology, Professor, 大学院・生命理工学研究科, 教授 (90192492)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
KeywordsTetrahydrobiopterin / knockout mice / 6-pyruvoyltetrahydropterin synthase / Malignant hyperphenylalaninemia / Dopamine β-hydroxylase / lymphocyte / L-DOPA / 6-PTPS
Research Abstract

Tetrahydrobiopterin (BH4) synthesized from GTP In viva Is an essential cofactor for phenylalanine hydroxylase which converts phenylalanin to tyrosirie, tyrosine hydroxylase and tryptophan hydroxylase which are rate-limiting enzymes for catecholamine and serotonin biosynthesis, respectively. Also BH4 is known as a cofactor for nitric oxide synthase.
1,We established 6-pyruvoyltetrahydropterin synthase (PTPS) knockout (PTPS-KO) mice by gene targeting, which catalyzes the second step of BH4 biosynthesis, previously. In this project we grafted the thymus from PTPS-KO embryos to nude mice, and also grafted blood stem cells to radiated CsilsL/6 mice. We analyzed differentiated lymphocytes, by surface antigens by FACS, mixture assay, PEA assay, LPS and ConA stimulation. However, we did not detect significant difference between lymphocytes from homozygotes and those from wild types.
2,We Injected BH4, L-DOPA and 5-HTP Intraperitonealy to PTPS-KO neonates respectively and assayed monoamine contents, TH and TPH activity. In the brain of L-DOPA and 5-HTP Injected mice, monoamine content rapidly elevated and was metabolized, compare to BH4 supplementation.
3,We established several transgenlc mice lines using human PTPS cDNA under the control of 5.8 kb mouse dopamine β-hydroxylase genomic promoter (DPS). A DPS transgenlc line crossed to PTPS-KO heteroxygotes and successively rescued them after weaning (PTPS-KO, DPSG). PTPS-KO, DPS6 mice showed evident developmental retardation. BW of PTPS-KO, DPS6 is 60 % of those of wild type littermates. In 8 to 12 weeks, plasma phenylalanine content of PTPS-KO, DPS6 mice were 37.4 times higher than those of wild type mice.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Ohtsuki M, et al.: "CAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells."Life Sci.. 70. 2187-2198 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 加藤大也 他: "ヒト月斉静脈内皮細胞におけるテトラヒドロビオプリテリンの生合成調節-サイトカイン刺激によるBH4産生誘導のCAMPによる抑制"藤田学園医学会誌. 26. 83-88 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shiraishi H, et al.: "C GMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells."J.Pharmacol.Sci.. 93. 268-271 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 一瀬(鷲見)千穂 他: "テトラヒドロビオプテリンによるモノアミンの生合成調節-6ピルボイルテトラヒドロプテリン合成酵素遺伝子ノックアウトマウスの研究から-"藤田学園医学会誌. 27. 17-24 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 白石弘章 他: "血管内皮細胞におけるテトラヒドロビオプリテリンの生合成調節とその意義"日薬理誌 120補冊1. 73-75 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sumi, Ichinose C, et al.: "Catecholamine research : From molecular insights to clinical medicine"Plenum Publishers. 431-434 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ichinose H, et al.: "Genetics of movement disorders"Elsevier Science. 419-428 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sumi, Ichinose C, et al.: "Pterins, Folates and Neurotransmitters in Molecular Medicine"SPS Verlagsgesellschaft. 109-113 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ohtsuki M., et al.: "cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells."Life Sci.. 70. 2187-2198 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shiraishi H., et al.: "cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial"J.Pharmacol.Sci.. 93. 265-271 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kato D.,: "The regulation of tetrahydrobiopterin biosynthesis in human umbilical vein endothelial cells-the suppression by CAMP signaling of cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells-"Bulletin of the Fujita Medical Society. 26. 83-88 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sumi Ichinose C.,: "A novel regulatory system for monoamines by tetrahydrobiopterin"Bulletin of the Fajita Medical Society. 27. 17-24 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sumi-Ichinose C., et al.: "tetrahydrobiopterin differently regulates the biosynthesis of catecholamines and serotonin, implication in neuro psychiatric disorders."Catecholamine research : From molecular insights to clinical medicine.(Plenum publishers). 431-434 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ichinose H., et al.: "Dopa-responsive dystonia"Genetics of movement disorders, (Elsevier Science). 419-428 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sumi-Ichinose C., et al.: "Effect of acute and repeated administration of tetrahydrobiopterin to 6-pyruvoyltetrahydropterin synthase Knockout mice"Pterins, Foliates and Neurotransmitters in Molecular Medicine (SPS Verlagsgesellschaft. 109- (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shiraishi H., et al.: "cGMP inhibits GTP cycloydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endotherial cells."J.Pharmacol.Sci.. 93. 265-271 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 加藤 大也 他: "ヒト臍帯静脈内皮細胞におけるテトラヒドロビオプテリンの生合成調節-サイトカイン刺激によるBH4産生誘導のcAMPによる抑制"藤田学園医学会誌. 26. 83-88 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] 一瀬(鷲見)千穂 他: "テトラヒドロビオプテリンによるモノアミンの生合成調節-6-ピルボイルテトラヒドロプテリン合成酵素遺伝子ノックアウトマウスの研究から-"藤田学園医学会誌. 27. 17-24 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sumi-Ichinose C., et al.: "Catecholamine research : From molecular Insights to clinical medicine (Advances In Behavioral Biology, 53)"Tetrahydrobiopterin differentially regulates the biosynthesis of catecholamines and serotonin, implication in neuropsychiatric disorders.. (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ohtsuki M. et al.: "cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells"Life Sci.. 70. 2187-2198 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 黒田理佐 他: "テトラヒドロビオプテリン欠損マウスにおけるカテコールアミンおよびセロトニンの生合成障害"藤田医学会誌. 25. 15-20 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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