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Adrenoleukodystrophy: effect of bone marrow transplantation in abcd1-deficient mouse

Research Project

Project/Area Number 16K09961
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionUniversity of Toyama

Principal Investigator

MORITA MASASHI  富山大学, 大学院医学薬学研究部(薬学), 准教授 (20191033)

Co-Investigator(Kenkyū-buntansha) 長井 良憲  富山県立大学, 工学部, 教授 (30431761)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords副腎白質ジストロフィー / 神経変性疾患 / ペルオキシソーム / 骨髄移植 / ABCタンパク質 / ミクログリア / NLRP3 / 極長鎖脂肪酸 / ABCD1 / 先天代謝異常
Outline of Final Research Achievements

X-linked adrenoleukodystrophy patients display cerebral inflammatory demyelination. Although very long chain fatty acids (VLCFA) accumulation is thought to be the main culprit underlying the pathogenesis, the mechanisms by which the VLCFA causes demyelinating neurodegeneration have not yet been elucidated. At present, bone marrow transplantation (BMT) is effective in halting disease progression. In our BMT experiments, the VLCFA plasma level significantly decreased and donor-derived bone marrow cells (BMDM) were engrafted in the brain as macrophage-like cells. However, the VLCFA levels in recipient mouse brain was not reduced by BMT. In the recipient mouse brain, some cholesterol metabolism-related genes were changed by BMT. These results suggest that BMDMs may interact with resident glial cells or endothelial cells, and thus may attenuate the cholesterol metabolic abnormality, which in turn suppresses neuroinflammation.

Academic Significance and Societal Importance of the Research Achievements

副腎白質ジストロフィーは発病メカニズムが明らかになっていない遺伝性の神経変性疾患で、日本でも毎年新生児約20人程度の割合で患者がいると推定され、治療薬開発は僅々の重要課題である。本研究では、本疾患がペルオキシソーム機能欠損による極長鎖脂肪酸代謝異常とともに、コレステロール代謝異常が発病に関わっている可能性を明らかにした。将来的にはコレステロール代謝異常を標的とした炎症性脱随を予防するという新しい視点から本疾患の発病抑制薬の開発が期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (17 results)

All 2018 2017 2016

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 1 results) Presentation (13 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results)

  • [Journal Article] Stability of the ABCD1 Protein with a Missense Mutation: A Novel Approach to Finding Therapeutic Compounds for X-Linked Adrenoleukodystrophy.2018

    • Author(s)
      Morita M, Matsumoto S, Sato A, Inoue K, Kostsin DG, Yamazaki K, Kawaguchi K, Shimozawa N, Kemp S, Wanders RJ, Kojima H, Okabe T, Imanaka T
    • Journal Title

      JIMD Rep

      Volume: 44 Pages: 23-31

    • DOI

      10.1007/8904_2018_118

    • ISBN
      9783662586167, 9783662586174
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Profiling and Imaging of Phospholipids in Brains of Abcd1-Deficient Mice2018

    • Author(s)
      Hama K, Fujiwara Y, Morita M, Yamazaki F, Nakashima Y, Takei S, Takashima S, Setou M, Shimozawa N, Imanaka T, Yokoyama K.
    • Journal Title

      Lipids

      Volume: 53 Issue: 1 Pages: 85

    • DOI

      10.1002/lipd.12022

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characterization of human ATP-binding cassette protein subfamily D reconstituted into proteoliposomes.2018

    • Author(s)
      Okamoto T, Kawaguchi K, Watanabe S, Agustina R, Ikejima T, Ikeda K, Nakano M, Morita M, Imanaka T.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 496 Issue: 4 Pages: 1122-1127

    • DOI

      10.1016/j.bbrc.2018.01.153

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Effect of Lorenzo's Oil on Hepatic Gene Expression and the Serum Fatty Acid Level in abcd1-Deficient Mice.2017

    • Author(s)
      Morita M, Honda A, Kobayashi A, Watanabe Y, Watanabe S, Kawaguchi K, Takashima S, Shimozawa N, Imanaka T.
    • Journal Title

      JIMD Rep.

      Volume: 38 Pages: 67-74

    • DOI

      10.1007/8904_2017_32

    • ISBN
      9783662566091, 9783662566107
    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Transport mechanism of vitamin B12 from lysosome to cytosol mediated by ABC transporter ABCD42018

    • Author(s)
      Kitai K, Kawaguchi K, Morita M, Imanaka T, So T.
    • Organizer
      The 3rd TAA-Pharm Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Adrenoleukodystrophy: bone marrow transplantation in the X-ALD mice model and impact of microglia on disease pathogenesis2018

    • Author(s)
      Kaizawa T, Yoda T, Morita M, Imanaka T, So T.
    • Organizer
      The 3rd TAA-Pharm Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ペルオキシソーム膜ABCトランスポーターABCD1がもつアシルCoAチオエステラーゼ活性の解析2018

    • Author(s)
      川口甲介、北井克樹、守田雅志、今中常雄、宗孝紀
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ペルオキシソーム機能と細胞内コレステロール代謝の関連性2018

    • Author(s)
      富田勇、宮澤美優、山田祥太朗、守田雅志、宗孝紀.
    • Organizer
      日本薬学会北陸支部第130回例会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ピレン修飾脂肪酸を用いた新規ペルオキシソーム脂肪酸β酸化活性及び脂肪酸合成活性の測定法2018

    • Author(s)
      佐藤英晶、守田雅志、渡辺志朗、今中常雄、宗孝紀
    • Organizer
      日本薬学会北陸支部第130回例会
    • Related Report
      2018 Annual Research Report
  • [Presentation] リソソーム膜ABCトランスポーターABCD4を介したビタミンB12輸送機構の解析2018

    • Author(s)
      北井克樹、川口甲介、岡元拓海、守田雅志、今中常雄、宗孝紀
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 骨髄移植による副腎白質ジストロフィー 発症抑制機構:移植マウス中枢神経系の生化学的解析2017

    • Author(s)
      守田 雅志,大山 拓郎,冨田 勇, 螺澤 太郎, 松本 隼,渡辺 志朗, 渡邉 康春,長井 良憲,高津 聖志,山本 誠士,石井 陽子,笹原 正清,今中 常雄
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-26
    • Related Report
      2016 Research-status Report
  • [Presentation] 副腎白質ジストロフィー: 骨髄移植による神経変性 抑制効果の解析2017

    • Author(s)
      守田雅志,大山拓郎,螺澤太郎, 依田大輝,渡辺志朗, 今中常雄
    • Organizer
      2017年度生命科学系学会合同年次大会(神戸)
    • Related Report
      2017 Research-status Report
  • [Presentation] ペルオキシソーム脂肪酸β酸化の活性化 を指標とした副腎白質ジストロフィー治療候補化合物の探2017

    • Author(s)
      守田雅志, 冨田海斗, 佐藤瑛晶, 松本隼, 渡辺志朗, 下澤伸行, 今中常雄
    • Organizer
      第59回日本先天代謝異常学会(埼玉)
    • Related Report
      2017 Research-status Report
  • [Presentation] 副腎白質ジストロフィー:骨髄移植による神経変性発症抑制2017

    • Author(s)
      螺澤太郎, 大山拓郎,冨田勇, 松本隼,渡辺志朗, 今中常雄,守田雅志
    • Organizer
      日本生化学会北陸支部第35回大会(金沢)
    • Related Report
      2017 Research-status Report
  • [Presentation] Abcd1欠損マウスへの骨髄移植:レシピエントマウス各組織の生化学的解析2016

    • Author(s)
      守田雅志,大山拓郎,冨田 勇,渡邉靖春,長井良憲、渡辺志朗,小林博司,大橋十也,高津聖志,今中常雄
    • Organizer
      第58回日本先天代謝異常学会総会
    • Place of Presentation
      東京
    • Year and Date
      2016-10-27
    • Related Report
      2016 Research-status Report
  • [Presentation] Development of therapeutic drugs for X-linked adrenoleukodystrophy.2016

    • Author(s)
      Morita M, Imanaka T.
    • Organizer
      The First International Symposium on Toyama-Asia-Africa Pharmaceutical Network (1st TAA-Pharm Symposium)
    • Place of Presentation
      富山
    • Year and Date
      2016-09-12
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 骨髄移植による副腎白質ジストロフィー 発症抑制機構の解明:レシピエントマウスの生化学的解析2016

    • Author(s)
      大山拓郎,冨田 勇, 螺澤太郎, 松本 隼,守田雅志,渡辺志朗, 渡邉康春 ,長井良憲,高津聖志,山本誠士,石井陽子,笹原正清,今中常雄
    • Organizer
      日本薬学会北陸支部第128回例会
    • Place of Presentation
      金沢
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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