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mTORC1 as a therapeutic target for XLH

Research Project

Project/Area Number 17K10092
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionOsama Woman's and Children's Hospital

Principal Investigator

Masanobu Kawai  地方独立行政法人大阪府立病院機構大阪母子医療センター(研究所), 環境影響部門, 主任研究員 (50598117)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsリン / インスリン / PTEN / mTORC1 / FGF23 / phosphate / AKT / X連鎖性低リンくる病 / X連鎖性低リン性くる病 / 分枝鎖アミノ酸
Outline of Final Research Achievements

Fibroblast growth factor 23 (FGF23) has been centric to the regulation of phosphate (Pi) metabolism; however, the regulatory network of FGF23 in osteocytes has not yet been defined in detail. In addition, accumulating evidence demonstrates the role for insulin signaling in the regulation of Fgf23 in bone. We herein investigated the role of PTEN (phosphatase and tensin homolog deleted from chromosome 10) in this regulation. We created mice lacking Pten expression mainly in osteocytes by crossing Pten-flox mice with Dmp1-Cre mice. The lack of Pten in the osteocytes of these mice was associated with decreased serum Fgf23 levels, which, in turn, resulted in reductions of urinary Pi excretion and elevations of serum Pi levels. Mechanistically, the insulin-induced suppression of Fgf23 expression was reversed in cells treated with the mTORC1 inhibitor, rapamycin.

Academic Significance and Societal Importance of the Research Achievements

近年、リン代謝制御機構が明らかとなってきており、インスリンシグナルによるFGF23制御機構が注目されている。臨床的には、インスリン抵抗性をきたすような肥満患者では、FGF23濃度が増加しており、肥満の病態形成におけるFGF23の役割が明らかになってきているが、その分子機序は不明であった。本研究成果は、インスリンによるFGF23制御機構の分子機序を明らかにしたものであり、骨細胞におけるインスリンシグナルが肥満症の病態形成に与える影響を理解する上で、重要な意味があると考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (20 results)

All 2020 2019 2018 2017

All Journal Article (12 results) (of which Peer Reviewed: 12 results,  Open Access: 5 results) Presentation (8 results) (of which Int'l Joint Research: 1 results,  Invited: 5 results)

  • [Journal Article] Policy Statement of Enteral Nutrition for Preterm and Very Low Birthweight Infants.2020

    • Author(s)
      Mizuno K, Shimizu T, Shinobu Ida, Ito S, Inokuchi M, Ohura T,Okumura A, KawaiM,Kikuchi T, Sakurai M, Sugihara S, Suzuki M,Takitani K,Tanaka D,Mushiake S,Yoshiike N,Kodama H,Kazuo Okada K, Tsutsumi C, Hara M, Hanawa Y,Kawakami K, Inomata H, Oguni T,Bito Y,Uchida K, Akihide Sugiyama A.
    • Journal Title

      Pediatr Int.

      Volume: 62 Issue: 2 Pages: 124-127

    • DOI

      10.1111/ped.14067

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients2020

    • Author(s)
      Michigami T, Tachikawa K, Yamazaki M, Kawai M, Kubota T, Ozono K
    • Journal Title

      Calcif Tissue Int

      Volume: 106 Issue: 3 Pages: 221-231

    • DOI

      10.1007/s00223-019-00626-w

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MIRAGE syndrome caused by a novel missense variant (p.Ala1479Ser) in the SAMD9 gene.2019

    • Author(s)
      Onuma S, Wada T, Araki R, Wada K, Tanase-Nakao K, Narumi S, Fukui M, Shoji Y, Etani Y, Ida S, Kawai M.
    • Journal Title

      Hum Genome Var.

      Volume: 7 Issue: 1 Pages: 4-4

    • DOI

      10.1038/s41439-020-0091-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genotype-phenotype correlation analysis in Japanese patients with Noonan syndrome2019

    • Author(s)
      Shoji Y, Ida S, Niihori T, Aoki Y, Okamoto N, Etani Y, Kawai M.
    • Journal Title

      Endocrine Journal

      Volume: 66 Issue: 11 Pages: 983-994

    • DOI

      10.1507/endocrj.EJ18-0564

    • NAID

      130007751668

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] For Debate: When is Selenium Deficiency Suspected and When is Its Measurement Indicated?2019

    • Author(s)
      Masanobu Kawai
    • Journal Title

      Pediatr Endocrinol Rev.

      Volume: 16 Pages: 307-310

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Intestinal clock system regulates skeletal homeostasis.2019

    • Author(s)
      Kawai M, Kinoshita S, Yamazaki M, Yamamoto K, Rosen CJ, Shimba S, Ozono K, Michigami T
    • Journal Title

      JCI Insight

      Volume: Mar 7;4(5)

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B.2019

    • Author(s)
      Yamamoto K, Kawai M, Yamazaki M, Tachikawa K, Kubota T, Ozono K, Michigami T.
    • Journal Title

      Hum Mol Genet

      Volume: 28 Issue: 7 Pages: 1183-1198

    • DOI

      10.1093/hmg/ddy428

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia.2019

    • Author(s)
      Hasegawa Y, Kawai M, Bessho K, Yasuda K, Ueno T, Satomura Y, Konishi A, Kimura T, Ikeda K, Tachibana M, Miyoshi Y, Michigami T, Kondou H, Ozono K
    • Journal Title

      Hepatol Res

      Volume: 49 Issue: 3 Pages: 314-323

    • DOI

      10.1111/hepr.13245

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Visceral adipose tissue increases shortly after the cessation of GH therapy in adults with Prader-Willi syndrome.2018

    • Author(s)
      Koizumi M, Ida S, Shoji Y, Nishimoto Y, Etani Y, Kawai M
    • Journal Title

      Endocr J

      Volume: 65 Pages: 1127-1137

    • NAID

      130007537278

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Phosphate as a Signaling Molecule and Its Sensing Mechanism.2018

    • Author(s)
      Michigami T, Kawai M, Yamazaki M, Ozono K
    • Journal Title

      Physiol Rev

      Volume: 98 Issue: 4 Pages: 2317-2348

    • DOI

      10.1152/physrev.00022.2017

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Thyroid hormone status in patients with severe selenium deficiency2018

    • Author(s)
      Kawai M, Shoji Y, Onuma S, Etani Y, Ida S
    • Journal Title

      Clinical Pediatric Endocrinology

      Volume: 27 Issue: 2 Pages: 67-74

    • DOI

      10.1297/cpe.27.67

    • NAID

      130006701338

    • ISSN
      0918-5739, 1347-7358
    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Extracellular Phosphate Induces the Expression of Dentin Matrix Protein 1 Through the FGF Receptor in Osteoblasts.2017

    • Author(s)
      Nishino J, Yamazaki M, Kawai M et al.
    • Journal Title

      J Cell Biochem.

      Volume: 118 Issue: 5 Pages: 1151-1163

    • DOI

      10.1002/jcb.25742

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Clock genes and bone and mineral metabolism2019

    • Author(s)
      Masanobu KAWAI
    • Organizer
      9th International Conference on Children’s Bone Health (ICCBH)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 腸管生物時計はVDR依存性カルシウム吸収を制御し、その破綻は骨量減少を引き起こす2018

    • Author(s)
      3.川井正信、木下さおり、山崎美和、山本景子、大薗恵一、道上敏美
    • Organizer
      第36回日本骨代謝学会
    • Related Report
      2018 Research-status Report
  • [Presentation] セレンの生物学2017

    • Author(s)
      川井正信
    • Organizer
      第51回日本小児内分泌学会学術集会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 腸管生物時計はVDR依存性カルシウム吸収を制御し、その破綻は骨量減少を引き起こす2017

    • Author(s)
      川井正信
    • Organizer
      第51回日本小児内分泌学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 生活リズムと健やかな成長2017

    • Author(s)
      川井正信
    • Organizer
      第51回日本小児内分泌学会学術集会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] ビタミンD欠乏症2017

    • Author(s)
      川井正信
    • Organizer
      第44回 日本小児栄養消化器肝臓学会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 生活リズムと健やかな成長2017

    • Author(s)
      川井正信
    • Organizer
      第37回マグネシウム学会学術集会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] アンドロゲン不応症2017

    • Author(s)
      川井正信
    • Organizer
      第6回DSDセミナー in 大阪
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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