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Production and application of novel model animals with an oxidative stress

Research Project

Project/Area Number 08557014
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Pathological medical chemistry
Research InstitutionGRADUATE SCHOOL OF PHARMACEUTICAL SCIENCES,THE UNIVERSITY OF TOKYO

Principal Investigator

ARAI Hiroyuki  THE UNIV.TOKYO,GRADUATE SCHOOL OF FARM.SCI., ASSOCIATE PROFESSOR, 大学院・薬学系研究科, 助教授 (40167987)

Co-Investigator(Kenkyū-buntansha) SUZUKI Hiroshi  CSK RESEARCH PARK,DEV.TECHNOLOGY PRICIPAL INVESTIGATOR, 発生工学部, 研究主査
AOKI Junken  THE UNIV.TOKYO,GRADUATE SCHOOL OF FARM.SCI., ASSISTANT PROFESSOR, 大学院・薬学系研究科, 助手 (20250219)
INOUE Keizo  THE UNIV.TOKYO,GRADUATE SCHOOL OF FARM.SCI., PROFESSOR, 大学院・薬学系研究科, 教授 (30072937)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 1998: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1997: ¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 1996: ¥6,700,000 (Direct Cost: ¥6,700,000)
KeywordsVITAMINE / OXIDATIVE STRESS / KNOCKOUT MOUSE / BERGMANN GLIA / 小脳 / プルキンエ細胞 / バーグマングリア細胞 / 輸送蛋白質 / 基質特異性
Research Abstract

Vitamin E (a-tocopherol) is a fat-soluble antioxidant that is transported by plasma lipoproteins in the body. a-tocopherol taken up by the liver with lipoprotein is thought to be re-secreted into the plasma in very low density lipoprotein (VLDL), alpha-tocopherol transfer protein (alphaTTP), which was recently identified as a product of the causative gene for familial isolated vitamin E deficiency, is a cytosolic liver protein and plays an important role in the efficient recycling of plasma vitamin E.Using cell culture system, we found that the secretion of alpha-tocopherol is more efficient in cells expressing alphaTTP than in matched cells lacking alphaTTP.Brefeldin A, which inhibits VLDL secretion by disrupting the Golgi apparatus, has no effect on alpha-tocopherol secretion, indicating that alphaTTP-mediated alpha-tocopherol secretion is not coupled to VLDL secretion. Among other agents tested, only 25-hydroxycholesterol, a modulator of cholesterol metabolism, inhibits alpha-tocoph … More erol secretion. These results suggest that alphaTTP functions to stimulate secretion of cellular alpha-tocopherol into the extracellular medium and that the reaction utilizes a novel non-Golgi mediated pathway which may be linked to cellular cholesterol metabolism or transport. We examined the structural characteristics of vitamin E analogs required for recognition by alphaTTP.Interestingly, there is a linear relationship between the relative affinity and the known biological activity obtained from the rat resorption-gestation assay. Thus the affinity of vitamin E analogs for alphaTTP is one of the critical determinants of their biological activity. alphaTTP is exclusively expressed in the liver, but the message for alphaTTP was detectable at low levels in some rat tissues including brain, spleen, lung and kidney. In the brain, the alphaTTP transcript is detected predominantly in the cerebellar cortex, as revealed by in situ hybridization histochemistry. In the celebellar cortex, the hybridization signals are detected mostly in the Bergmann glial cells. We have recently succeeded in establishing the knock out mice for alphaTTP.The plasma vitamin E level of the mice is almost undetectable and that of heterozygote is about half that of wild type mice. These data clearly demonstrate that alphaTTP is a major determinant of plasma vitamin E level. Less

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Traber,M.G.et al.: "Molecular mechanism of vitamin E transport" Annual Review of Nutrition. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hosomi,A.et al.: "Localization of α-tocopherol transfer protein in rat brain" Neuroscience Letters. 256. 159-162 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Adachi,H.et al.: "Expression cloning of a novel scavenger receptor from human cells" Journal of Biological Chemistry. 272. 31217-31220 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matzuzawa,A.et al.: "Protection against oxidative stress-induced cell death by intracellular platelet-activating factor-acetylhydrolase II" Journal of Biological Chemistry. 272. 32315-32320 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Arita M.et al.: "α-Tocopherol transfer protein stimulates the secretion of α-tocopherol from a cultured liver cell line through a brefeldin A-insensitive pathway" Proc.Natl.Acad.Sci.USA. 94. 12437-12441 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokota,T et al.: "Retinitis pigmentosa and ataxia caused by a mutation in the gene for the α-tocopherol transfer protein" New England Journal of Medicine. 335. 1770-1770 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.G.Traber and H.Arai: "Molecular mechanism of vitamin E transport" Annu.Rev.Nutri.(in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] A.Hosomi, K.Goto, H.Kondo, T.Iwatsubo, T.Yokota, M.Ogawa, M.Arita, J.Aoki, H.Arai, K.Inoue: "Localization of alpha-tocopherol transfer protein in rat brain" Neuroscience Letters. 256. 159-162 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Adachi, M.Tsujimoto, H.Arai, and K.Inoue: "Expression cloning of a novel scavenger receptor from human endothelial cells" J.Biol.Chem.272. 31217-31220 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] A.Matsuzawa, K.Hattori, J.Aoki, H.Arai, and K.Inoue: "Protection against oxidative stress-induced cell death by intracellular platelet-activating factor-acetylhydrolase II" J.Biol.Chem.272. 32315-32320 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.Arita, K.Nomura, H.Arai and K.Inoue: "alpha-Tocopherol transfer protein stimulates the secretion of a-tocopherol from a cultured liver cell line through a brefeldin A-insensitive pathway" Proc.Natl.Acad.Sci.USA. 94. 12437-12441 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Yokota, T.Shiojiri, T.Gotoda and H.Arai: "Retinitis pigmentosa and ataxia caused by a mutation in the gene for the alpha-tocopherol-transfer protein" New Engl.J.Med.335. 1770 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Arita,M.et al.: "Binding of α-tocopherylquinone,an oxidized from of δ-tocopherol toglutathione-S-transferase in the liver cytosol" FEBS Letters. 436. 424-426 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hosomi,A.et al.: "Localization of δ-tocopherol transfer protein in rat brain" Neuroscience Letters. 256. 159-162 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Matsuzawa Atsushi et al.: "Protection against oxidative stress-induced cell death by intracellular platelet-activating factor-acetylhydrolase II" Journal of Biological Chemistry. 272巻. 32315-32320 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Arita Makoto et al.: "α-Tocopherol transfer protein stimulates the secretion of α-tocopherol from a cultured liver cell line through a brefeldin A-insensitive pathway" Proceedings of National Academy of Science USA. 94巻. 12437-12441 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kim H.-S.et al.: "Age-related changes of a-tocopherol transfer protein expression in rat liver" J Nutr.Sci Vitaminol.42. 11-18 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yokota T.et al: "Retinitis Pigmentosa and Ataxia Caused by a Mutation in the Gene for the α-Tocopherol Transfer Protein" N.Engl.J.Med.335. 1770-1771 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 新井洋由: "ビタミンE輸送タンパク質と先天性ビタミンE欠乏症" 日本油化学会誌, 10 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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