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Multiple approaches of the therapy for lysosomal diseases affected with central nervous system

Research Project

Project/Area Number 13470164
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionOsaka University

Principal Investigator

SAKAI Norio (2003)  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30314313)

乾 幸治 (2001-2002)  大阪大学, 医学系研究科, 助教授 (90175208)

Co-Investigator(Kenkyū-buntansha) WADA Kazuko  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30294094)
平野 慎也  大阪大学, 医学部附属病院, 医員(臨床研究)
酒井 規夫  大阪大学, 医学系研究科, 助手 (30314313)
島 雅昭  大阪大学, 医学系研究科, 講師 (10252660)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2003: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2002: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2001: ¥8,900,000 (Direct Cost: ¥8,900,000)
Keywordslysosomal disease / psychosine / T cell death associated gene 8 / Krabbe disease / Farber disease / saposin A / Molecular shaperon / ガラクトセレブロシダーゼ / 遺伝子変異解析 / 蛋白質発現系 / DHPLC法
Research Abstract

Lysosomal diseases were caused by the accumulation of undigested substrates within lysosome. The lysosomal diseases affected in the central nervous system were hard to treat because the recombinant enzyme could not be entered through blood brain barrier. We tried several projects to approach the therapy of these disease, as follows ;
1)Express affected enzyme: We tried to construct for the normal galactocerebrosidase to express in large-scale in yeast, however the ratio of expression was not good enough.
2)Inhibition of synthetic enzyme of sphingolipid : We realize that cycloserine was confirmed to inhibit production of psychosine. We will check dose dependency for the effect of cycloserine.
3)Molecular shaperon : Saposine A was proven to be the activator of galactocerebrosidase and might be shaperon for it. We were succeeded in express saposin A in yeast expression system. Purified saposin A was able to activate β-glucosidase and galactocerebrosidase.
4)Activation of affected enzyme: The produced saposin A might be able to bind enzyme and stabilyze them. We are analyzing this effect in vivo.
5)Block apoptosis cascade : We check the expression profile of TDAG8 and analyzed the effect of antibody against TDAG8.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Yamada M, Inui K, Hamada D, Nakahira K, Yanagihara K, Sakai N, et al.: "Analysis of recombinant human Saposin A expressed by Pichia pastoris"BBRC. In press.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kokubu C, Wilm C, Kokubu T, Wahl M, Rodrigo I, Sakai N, et al.: "Undulated short-tail Deletion Mutation in the Mouse Ablates Pax1 and Leads to Ectopic Activation of Neighboring Nkx2-2 in Domains that Normally Express Pax1"Genetics. 165. 299-307 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Muramatsu T, Sakai N, Yanagihara I, Inui K: "Mutatinal analysis of the acid ceramidase genen in the Japanese patients with Farber lipogranulomatosis"J Inherit Meta Dis. 25. 585-592 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Akagi M, Inui K, Tsukamoto H, Sakai N, Muramatsu T, Yamada M, Matsuzaki: "A point mutation of mitochondrial ATPase 6 gene in Leigh syndrome"Neuromuscul Disord. 12(1). 53-55 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inui K, Akagi M, Ono J, Tsukamoto H, Shimono K, Mano T, Imai K, Yamada M, Muramatsu T, Sakai N, Okada S: "Mutational analysis of MECP2 in Japanese patients with atypical Rett syndrome"Brain Dev.. 23(4). 212-215 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsukamoto H, Yamamoto T, Nishigaki T, Sakai N, Nanba E, Ninomiya H, Ohno K, Inui K, Okada S: "SSCP analysis by RT-CR for the prenatal diagnosis of Niemann-Pick disease type C"Prenat Diagn.. 21(1). 55-7 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamada M, Inui K, Hamada D, Nakahira K, Yanagihara K, Sakai N, Nishigaki T, Ozono K,, Yanagihara I: "Analysis of recombinant human Saposin A expressed by Pichia pastoris"BBRC. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kokubu C, Wilm C, Kokubu T, Walil M, Rodrigo I, Sakai N, Santagati F, Hayashizaki Y, Suzuki M, Yamamura K, Abe K, Imai K: "Undulated short-tail Deletion Mutation in the Mouse Ablates Paxi and Leads to Ectopic Activation of Neighboring NkxZ-2 in Domains that Normally Express Pax1"Genetics. 165. 299-307 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Muramatsu T, Sakai N, Yanagihara I, Inui, K: "Mutational analysis of the acid ceramidase genera in the Japanese patients with Farber lipogranulomatosis"J Inherit Meta Dis. 25. 585-592 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Akagi M, Inui K, Tsukamoto H, Sakai N, Muramatsu T, Yamada M, Matsuzaki K, Goto Y, Nonaka I, Okada S.: "A point mutation of mitochondrial ATPase 6 gene in Leigh syndrome."Neurornuscul Disord. 12(1). 53-55 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inui K, Akagi M, Ono J, Tsukamoto H, Shimono K, Mano T, Imai K, Yamada M, Muramatsu T, Sakai N, Okada S: "Mutational analysis of MECP2 in Japanese patients with atypical Rett syndrome"Brain Dev.. 23(4). 212-215 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsukamoto H, Yamamoto T, Nishigaki T, Sakai N, Nanba E, Ninomiya H, Ohno K, Inui K, Okada S.: "T SSCP analysis by RT CR for the prenatal diagnosis of Niemann-Pick disease type C."Prenat Diagn. 21(1). 55-57 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inui K, Yanagihara K, Otani K, Suzuki Y, Akagi M, Nakayama M, Ida H, Okada S.: "A new variant neuropathic type of Gauchefs disease characterized by hydrocephalus, corneal opacities, deformed toes, and fibrous thickening of spleen and liver capsules."J Pediatr.. 138(1). 137-139 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yanagihara I, Inui K, Yanagihara K, Park YD, Tanaka J, Ozono K, Okada S, Kurahashi H.: "Fluorescence in situ hybridization analysis of peripheral blood cells in Pearson marrow-pancreas syndrome."J Pediatr.. 139(3). 452-455 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kokubu, C., Wilm, Kokubu, T., Wahl, M., Sakai, N., et al.: "Undulated short-tail Deletion Mutation in the Mouse Ablates Pax1 and Leads to Ectopic Activation of Neighboring Nkx2-2 in Domains that Normally Express Pax1"Genetics. 165. 299-307 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 酒井規夫: "ムコリピドーシスII,III型"小児内科. 35. 494-497 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimizu S, Kawagishi R, Wada K, et al.: "Fetal homorrhage associated with congenitalintestinal atresia"J Obstet Gynaecol Res.. 29, 5. 312-316 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tomimatsu T, Fukuda H, Wada K, et al.: "Neonatal Bartter syndrome with unilateral multicystic dysplas tic kidney disease"Pediatr Nephrol.. 18, 4. 391-394 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kimura T, Usui N, Wada K, et al.: "Unilical cord ulser associated with fetal jejunal atresia : Report of 2 cases"Fetal Diagn Ther.. 18, 3. 144-147 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Muramatsu T, Sakai N, Yanagihara I, Inui, K: "Mutatinal analysis of the acid ceramidase genen in the Japanese patients with Farber lipogranulomatosis"J Inherit Meta Dis. (In press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Akagi M, Inui K, Tsukamoto H, Sakai N, et al.: "A point mutation of mitochondrial ATPase 6 gene in Leigh syndrome"Neuromuscul Disord. 12(1). 53-55 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Akagi M, Inui K, Tsukamoto H, Sakai N, et al.: "A point mutation of mitochondrial ATPase 6 gene in Leigh syndrome"Neuromuscul Disord. Et al.. 12. 53-55 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Inui K, Sakai N, Okada: "Mutational analysis of MECP2 in Japanese patients with atypical Rett syndrome"Brain Dev.. 23. 212-215 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsukamoto H, Yamamoto T, Nishigaki T, Sakai N, Inui K et al.: "SSCP analysis by RT-PCR for the prenatal diagnosis of Niemann-Pick disease type C"Prenat Diagn.. 21. 55-57 (2001)

    • Related Report
      2001 Annual Research Report

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

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