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Basic research of the new gene therapy for cerebral infarction

Research Project

Project/Area Number 13670669
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionJuntendo University

Principal Investigator

URABE takao  Juntendo University, Neurology, Assistant professor, 医学部, 講師 (60291663)

Co-Investigator(Kenkyū-buntansha) MIZUNO yoshikuni  Juntendo University, Neurology, Professor, 医学部, 教授 (30049043)
MOCHIZUKI hideki  Juntendo University, Neurology, Assistant professor, 医学部, 講師 (90230044)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsCerebral infarction / Ischemic neuronal death / Gene therapy / Apoptosis / Oxidative stress / Adeno-associated virus vector / Bone marrow transplantation / Microglia / アデノウイルスベクター / GAPDH
Research Abstract

Analysis of expressing apoptotic associated proteins in animal model of focal brain ischemia
To investigate the serial change and cellular localization of overexpressed Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), as well as whether or not overexpression of GAPDH is related to ischemia/reperfusion-induced neuronal apoptosis, we performed immunohistochemical study in a rat middle cerebral artery occlusion (MCAO) and reperfusion model. The current study distinctly demonstrated that nuclear translocation of overexpressed GAPDH occurred in both the ischemic core and the penumbra area soon after focal ischemia, and might be an early marker of ischemia/reperfusion-induced apoptotic neuronal death. Our findings suggest that GAPDH may play a critical role in the progression and expansion of ischemic neuronal damage.
To assess the distribution of microglia/macrophages in cerebral ischemia, we performed permanent focal ischemia using bone-marrow chimera mice known to express enhanced green fl … More uorescent protein (EGFP). This study directly showed the migration and distribution of bone marrow-derived monocytes/macrophages and the relationship between resident microglia and infiltrated hematogenous element in ischemic mouse brain.
Concentration and purification of Adeno-associated virus vector (AAV)
At present, we are promoting that Calbindin D28k cDNA is inserted into AAV.
Injection into the brain of animal model
We have already finished that Apaf 1 cDNA has been inserted into AAV, and adjusted the virus titer. Motchizuki H, et al. has been reported that the AAV-derived Apaf 1 dominant negative inhibitor prevents MPTP induced neuronal death as antiapoptotic gene therapy. At present, we are investigating that the AAV-derived Apaf 1 dominant negative inhibitor is injected into the gerbil hippocampus using a stereotaxic apparatus as antiapoptotic gene therapy for cerebral infarction.
Evaluation of oxidative stress as the marker of cell death
To assess the efficacy of gene therapy for ischemic neuronal death, we performed immunochemical study using antibodies of 4-hydoxy-2-nonenal (HNE)-modified protein and 8-hydroxy-2'-deoxyguanosine (8-OhdG) as a marker for oxidative stress. Less

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] Hideki Mochizuki et al.: "An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease"Proc Natl Acad Sci USA. 98. 10918-10923 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yumi Shimo-Nakanishi et al.: "Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese"Stroke. 32. 1481-1486 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ryota Tanaka et al.: "Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) is overexpressed in rat brain following focal ischemia"Journal of Cerebral Blood Flow and Meabolism. 22. 280-288 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Asuka Suzuki et al.: "Feasibility of ex vivo gene therapy for neurological disorders using the new retroviral vector GCDNsap packaged in the vesicular stomatitis virus G protein"Journal of Neurochemistry. 82. 953-960 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takao Urabe et al.: "Anticoagulant therapy with a selective thrombin inhibitor for acute cerebral infarction : usefulness of coagulation markers for evaluation of efficacy"Journal of Thrombosis and Thrombolysis. 13. 153-158 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ryota Tanaka et al.: "Migration of EGFP expressing bone marrow-derived microglia/macrophage into the mice brain following permanent focal ischemia"Neuroscience. 117. 531-539 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mochizuki H, Hayakawa H, Migita M, Shibata M, Tanaka R, Suzuki A, Shimo-Nakanishi Y, Urabe T, Yamada M, Tamayose K, Shimada T, Miura M, Yoshikuni M: "An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease"Proc Natl Acad Sci USA. 98. 10918-10923 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shimo-Nakanishi Y, Urabe T, Hattori N, Watanabe Y, Nagao T, Yokochi M, Hamamoto M, Mizuno Y: "Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese"Stroke. 32. 1481-1486 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanaka R, Mochizuki H, Suzuki A, Katsube N, Ishitani R, Mizuno Y, Urabe T: "Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) is overexpressed in rat brain follwing focal ischemia"Journal of Cerebral Blood Flow and Metabolism. 22. 280-288 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki A, Obi K, Urabe T, Hayakawa H, Yamada M, Kaneko S, Onodera M, Mizuno Y, Mochizuki H: "Feasibility of ex vivo gene therapy for neurological disorders using the new retroviral vector GCDNsap packaged in the vesicular stomatitis virus G protein"Journal of Neurochemistry. 82. 953-960 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Urabe T, Tanaka R, Noda K, Mizuno Y: "Anticoagulant therapy with a selective thrombin inhibitor for acute cerebral infarction : usefulness of coagulation markers for evaluation of efficacy"Journal of Thrombosis and Thrombolysis. 13. 153-158 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Piao L, Tanaka T, Nomiyama T, Nakajima K, Ogihara T, Miwa S, Urabe T, Watada T, Kawamori R: "Combined genotypes of ACE and NADPH oxidase p22phox associated with somatic mutation of mtDNA and carotid intima-media thickness in Japanese patients with type 2 diabetes mellitus"Curr Ther Res Clin Exp. 63. 842-852 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanaka R, Komine-Kobayashi M, Mochizuki H, Yamada M, Furuya T, Migita M, Shimada T, Mizuno Y, Urabe T: "Migration of EGFP expressing bone marrow-derived microglia/macrophage into the mice brain following permanent focal ischemia"Neuroscience. 117. 531-539 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hideki Mochizuki et al.: "An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease"Proc Natl Acad Sci USA. 98. 10918-110923 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimo-Nakanishi Y et al.: "Polymorphism of the llipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanease"Stroke. 32. 1481-1486 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ryota Tanaka et al.: "Glyceraldehyde-3-PhosphateDehydrogenase(GAPDH) is Overexpressed in Rat Brain Following Focal Ischemia"Journal of Cerebral Blood Flow and Metabolism. 22. 280-288 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Aska Suzuki et al.: "Feasibility of ex vivo gene therapy for neurological disorders using the new retroviral vector GCDNsap packaged in the vesicular stomatitis virus G protein"Journal of Neurochemistry. 82. 953-960 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takao Urabe et al.: "Anticoagulant therapy with a selective thrombin inhibitor for acute cerebral infarction : usefulness of coagulation markers for evaluation of efficacy"Journal of Thrombosis and Thrombolysis. 13. 153-158 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ryota Tanaka et al.: "Migration of EGFP expressing bone marrow-derived microglia/macrophage into the mice brain following permanent focal ischemia"Neurosciense. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hideki Mochizuki et. al.: "An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease"Proc Natl Acad Sci USA. 98. 10918-10923 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shimo-Nakanishi Y et. al.: "Polymorphism of the llipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanease"Stroke. 32. 1481-1486 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ryota Tanaka et. al.: "Induction of glyceraldehydes-3-phosphate dehydrogenase (GAPDH) expression in rat brain after focal ischemia/reperfusion"Journal of Cerebral Blood Flow and Metabolism. (in press). (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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