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Functional analysis of RXRB genetically identified as a susceptibility gene for systemic sclerosis

Research Project

Project/Area Number 19K08802
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53050:Dermatology-related
Research InstitutionTokai University

Principal Investigator

Oka Akira  東海大学, 医学部, 講師 (80384866)

Co-Investigator(Kenkyū-buntansha) 浅野 善英  東京大学, 医学部附属病院, 准教授 (60313029)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords全身性強皮症 / 遺伝子 / RNAシークエンシング / 繊維芽細胞 / RXRB / 細胞周期 / CRISPR/Cas9 / MHC / レチノイン酸
Outline of Research at the Start

研究代表者らは、retinoid X receptor beta (RXRB) 遺伝子上に、全身性強皮症 (SSc) の強いリスク (オッズ比 = 9.4)を伴うDNA上の変異を、世界で初めて特定することに成功した。この知見を元に、病態の原因解明ならびに新たな治療薬開発へ向け、このDNA変異の生物学的な機能を、患者由来繊維芽細胞やこのDNA変異を導入したマウスを用いることにより、明らかにする予定である。

Outline of Final Research Achievements

We have already identified a susceptibility mutation on the RXRB gene (retinoic acid receptor) that carries a strong genetic risk for systemic sclerosis (SSc). Therefore, they investigated the function of the mutation using fibroblasts isolated from patient-affected areas. Our studies showed that in the presence of retinoic acid, the expression of a gene group involved in the cell cycle was significantly increased only in cells with the mutation. This group containds cyclin-dependent kinase 1 (CDK1), and molecules targeting CDK1 have already shown promise as a treatment for SSc, it is strongly suggested that this mutation may be biologically involved in the pathogenesis of SSc.

Academic Significance and Societal Importance of the Research Achievements

全身性強皮症の遺伝学的なリスクと生物学的な機能を示した世界初の研究成果となる。すなわち、リスクの遺伝子型がすでに明らかになっている遺伝子とSScとの生物学的機能の関連を明らかにすることは、遺伝子型情報をベースとする、全く新しい診断、予防ならびに治療技術開発の可能性を秘めている。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (7 results)

All 2020 2019

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 2 results)

  • [Journal Article] Alopecia areata susceptibility variant in MHC region impacts expressions of genes contributing to hair keratinization and is involved in hair loss2020

    • Author(s)
      Oka A、Takagi A、Komiyama E、Yoshihara N、Mano S、Hosomichi K、Suzuki S、Haida Y、Motosugi N、Hatanaka T、Kimura M、Ueda M、Nakagawa S、Miura H、Ohtsuka M、Tanaka M、Komiyama T、Otomo A、Hadano S、Mabuchi T、Beck S、Inoko H、Ikeda S.
    • Journal Title

      EBioMedicine

      Volume: 57 Pages: 102810-102810

    • DOI

      10.1016/j.ebiom.2020.102810

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] HLA-B*39:01:01 is a novel risk factor for antithyroid drug-induced agranulocytosis in Japanese population2020

    • Author(s)
      Nakakura S, Hosomichi K, Uchino S, Murakami A, Oka A, Inoue I, Nakaoka H
    • Journal Title

      Pharmacogenomics J .

      Volume: 21 Issue: 1 Pages: 94-101

    • DOI

      10.1038/s41397-020-00187-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Overlapping systemic sclerosis and sarcoidosis with mutually exclusive disease activities: a case report and analysis of previous studies.2020

    • Author(s)
      Nakamura K, Sato S, Asano Y.
    • Journal Title

      Eur J Dermatol.

      Volume: 30 Pages: 50-52

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Serum delta-like 4 levels: A possible association with interstitial lung disease in systemic sclerosis.2020

    • Author(s)
      Fukui Y, Miyagawa T, Toyama S, Omatsu J, Hirabayashi M, Nakamura K, Yoshizaki A, Sato S, Asano Y.
    • Journal Title

      J Dermatol.

      Volume: 47 Issue: 4

    • DOI

      10.1111/1346-8138.15245

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Whole-exome sequencing in a Japanese pedigree implicates a rare non-synonymous single-nucleotide variant in BEST3 as a candidate for mandibular prognathism.2019

    • Author(s)
      Kajii TS, Oka A, Saito F, Mitsui J, Iida J.
    • Journal Title

      Bone.

      Volume: 122 Pages: 193-198

    • DOI

      10.1016/j.bone.2019.03.004

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Rituximab therapy is more effective than cyclophosphamide therapy for Japanese patients with anti-topoisomerase I-positive systemic sclerosis-associated interstitial lung disease.2019

    • Author(s)
      Ebata S, Yoshizaki A, Fukasawa T, Miura S, Takahashi T, Sumida H, Asano Y, Sato S.
    • Journal Title

      J Dermatol

      Volume: 46 Issue: 11 Pages: 1006-1013

    • DOI

      10.1111/1346-8138.15079

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Unique correlation profile of adiponectin and retinol-binding protein 4 in patients with systemic sclerosis.2019

    • Author(s)
      Asano Y, Masui Y, Toyama T, Sato S.
    • Journal Title

      J Dermatol.

      Volume: 46 Issue: 9 Pages: 819-820

    • DOI

      10.1111/1346-8138.14994

    • Related Report
      2019 Research-status Report
    • Peer Reviewed

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Published: 2019-04-18   Modified: 2023-01-30  

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