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Deficiency of Endothelin-Degrading Enzyme and Abnormality in Central Nervous System

Research Project

Project/Area Number 09670168
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionThe Tokyo Metropolitan Institute of Medical Science

Principal Investigator

ITOH Kohji  The Tokyo Metropolitan Institute of Medical Science, Clinical Genetics, Researcher, 臨床遺伝学研究部門, 研究員 (00184656)

Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1998: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1997: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsCentral nervous system / Neuropeptides / Protective protein / cathepsin A / Endothelin-1 / Big endothelin-1 / Endothelin-degrading enzyme / Serine carboxypeptidase / Antisense oligonucleotides / ビックエンドセリン1 / アンチセンスSオリゴDNA
Research Abstract

Protective protein/cathepsin A (PPCA) is a multifuctional glycoprotein that exerts the protective effects on lysososmal glycosidases and serine carboxypeptidase activity on a subset of neuropeptides. Galactosialidosis (GS) is a human PPCA deficiency with autosomal recessive genetic trait, accompanied by the simultaneous decrease of these enzyme activities and by the accumulation of their endogenous substrates. This disease shows very multiple clinial manifestations, including neurological abnormalities, such as cerebellar ataxia and myoclonus. From the research to elucidate the correlation between the catalytic functions of PPCA and the neurological abnormalities in the deficiency, new findings were obtained as follows ;
1. Histochemical analysis of the autopsied neurvous tissues derived from three adult/juvenile type GS patients was performed with anti-human PPCA, anti-endothelin-1(ET-1), a putative endogenous substrate of the catalytic activtity of PPCA, and anti-big endothelin-1(bigE … More T-1), the metabolic precursor protein of ET-1, The immunoreactivity against PPCA was hardly detected in the GS tissues. However, neurons and glial cells in the central nervous system, including cerebellum, hippocampal formation, spinal cord, etc, were found to show the increase in immunoreactivity against both ET-1 and bigET-1. These cells were also observed to contain relative high amount of PPCA in the healthy controls.
2. Antisense S-oligonucleotides, complementary to the 5' region of human and murine PPCA mRNA containing the translation initiation site, were selected to inhibit specifically the expression of PPCA functions in cultured cells by adding to the culture medium. The selected antisense S-oligonucleotides for murine PPCA gene was demonstrated to induce the increase of ET-1-like immunoreactivtiy in the type 1 astrocytes in cerebellar primary culture system.
3. For the purpose of the visualization of PPCA gene expression in living cells, fibroblastic cell lines were established, expressing the chimeric green fluorescent protein (GFP) gene fused to the PPCA eDNA.Expression of the wild-type and mutant PPCA fusion genes showed the different intracellular sorting according to their kind of mutations.This model system was applicable to visualize the intracellular
transport of lysosomal enzymes and to investigate the molecular bases of their deficiencies. Less

Report

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

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Itoh,K.: "Stabilizing effect of lysosomal β-galactosidase on the catalytic activity of protective protein/cathepsin A secreted by human platelets" Biochem.Biophys.Res.Commun.253. 228-234 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Itoh,K.: "Protective protein/cathepsin A loss in cultured cells derived from an early-infantile form of galactosialidosis patients homozygous for the A1184-G transition" Biochem.Biophys.Res.Commun.247. 12-17 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 伊藤 孝司: "ガラクトシアリドーシス" 別冊 日本臨床「先天代謝異常症候群」. 19. 407-410 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Itoh,K.: "Fetal diagnosis of galactosialidosis (protective protein/cathepsin A deficiency)" Clinica Chimica Acta. 266. 75-82 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Takiyama,N.: "Molecular form and subcellular distribution of acid β-galactosidase in fibroblasts from patients with Morquio B disease and galactosialdidosis" Brain and Development. 19. 126-130 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Naganawa,Y.: "Stable expression of protective protein/cathepin A-green fluorescent protein fusion genes in fibroblastic cell line with galactosialidosis" Biochemical J.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Itho, K., Miharu, N., Ohama, K., Mizoguchi, N., Sakura, N., Sakuraba, H.: "Fetal diagnosis of galactosialidosis (protective protein/cathepsin A deficiency)." Clin.Chim.Acta. 266. 75-82 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Takiyama, N., Itoh, K., Shimmoto, M., Nishimoto, M., Inui, K., Sakuraba, H., Suzuki, Y.: "Molecular form and subcellular distribution of acid beta-galactosidase in fibroblasts from patients with Morquio B disease and galactosialidosis." Brain Dev.19. 126-130 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Itoh, K., Shimmoto, M., Sakuraba, H.: "Galactosialidosis" Nippon Rinsho "Metabolic Inborn Errors". 19. 407-410 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Itho, K., Shimmoto, M., Utsumi, K., Mizoguchi, N., Miharu, N., Ohama, K., Sakuraba, H.: "Protective protein/cathepsin A loss in cultured cells derived from an early-infantile from of galactosialidosis patients homozygous for the A1184-G transition (Y395C mutation)." Biochem.Biophys.Res.Commun.247. 12-17 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Itoh, K., Naganawa, Y., Kamei, S., Shimmoto, M., Sakuraba, H.: "Stabilizing effect of lysosomal beta-galactosidase on the catalytic activity of protective protein/cathepsin A secreted by human platelets." Biochem.Biophys.Res.Commun.253. 228-234 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Naganawa, Y., Itoh, K., Shimmoto, M., Kamei, S., Takiguchi, K., Doi, H., Sakuraba, H.: "Sable expression of protective protein/cathepsin A-green fluorescent protein fusion genes in a fibroblastic cell line from a galactosialidosis patient." Biochemical J.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Itoh,K.: "Stabilizing effect of lysosomal β-galactosidase on the catalytic activity of protective protein/cathepsin A secreted by human platelets" Biochem.Biophys.Res.Commun.253. 228-234 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Itoh,K.: "Protective protein/cathepsin A loss in cultured cells derived from an early-infantile form of galactosialidosis patients homozygous for the A1184-G transition" Biochem.Biophys.Res.Commun.247. 12-17 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 伊藤 孝司: "ガラクトシアリドーシス" 別冊 日本臨床 「先天代謝異常症候群」. 19. 407-410 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Itoh,K.: "Fetal diagnosis of galactosialidosis (protective protein/cathepsin A deficiency)" Clinica Chimica Acta. 266. 75-82 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takiyama,N.: "Molecular form and subcellular distribution of acid β-galactosidase in fibroblasts from patients with Morquio B disease and galactosialidosis" Brain and Development. 19. 126-130 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Naganawa,Y.: "Stable expression of protective protein/cathepin A-green fluorescent protein fusion genes in fibroblastic cell line with galactosialidosis" Biochemical J.(in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] Itoh,K.: "Fetal diagnosis of galactosialidosis(protective protein/cathepsin A deficiency)" Clinica Chimica Acta. 266. 75-82 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 伊藤 孝司: "ガラクトシアリドーシス" 日本臨床「先天性代謝異常症候群」. (印刷中).

    • Related Report
      1997 Annual Research Report
  • [Publications] Takiyama,N.: "Molecular form and subcellular distribution of acid β-galactosidase in fibroblasts from patients with Morquio B disease and galactosialidosis." Brain and Development. 19. 126-130 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ozawa,H.: "Generation and characterization of mouse monoclonal antibodies specific for N-linked neutral oligosaccharides of glycoprotein." Archives Biochemistry and Biophysics. 342. 48-57 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Sakuraba,H.: "Immunocytochemical detection of accumulated substrates in cultured fibroblasts from patients with the infantile and adult Sandhoff disease." Clinica Chimica Acta. 265. 263-266 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Shimmoto,M.: "Generation and characterization of transgenic mouse expressing a human mutant α-galactosidase with an R301Q substitution causing a variant form of Fabry disease." FEBS Letters. 417. 89-91 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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