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表皮脂質の異常による魚鱗癬発症メカニズムの解明と新規治療薬開発への展開

Research Project

Project/Area Number 18H02832
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 53050:Dermatology-related
Research InstitutionNagoya University

Principal Investigator

秋山 真志  名古屋大学, 医学系研究科, 教授 (60222551)

Co-Investigator(Kenkyū-buntansha) 室 慶直  名古屋大学, 医学系研究科, 准教授 (80270990)
武市 拓也  名古屋大学, 医学系研究科, 講師 (30754931)
河野 通浩  秋田大学, 医学系研究科, 教授 (60319324)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords遺伝子 / 脂質 / 角化 / 魚鱗癬 / 表皮 / 皮膚バリア / 表皮脂質 / 魚燐癬
Outline of Annual Research Achievements

本研究計画では、以下の3つのプロジェクト、「常染色体劣性先天性魚鱗癬患者を対象とする病因解明とデータバンク、バイオバンク作成プロジェクト」、「常染色体劣性先天性魚鱗癬の病態解明プロジェクト」、「常染色体劣性先天性魚鱗癬の新規病因治療薬開発プロジェクト」を行って来た。今期間においては、前年度から引き続き、「常染色体劣性先天性魚鱗癬患者を対象とする病因解明とデータバンク、バイオバンク作成プロジェクト」と「常染色体劣性先天性魚鱗癬の病態解明プロジェクト」とを併行して施行した。さらに、本研究計画の最終ゴールである「常染色体劣性先天性魚鱗癬の新規病因治療薬開発プロジェクト」も施行した。具体的な今タームの研究実績の概要を以下に示す。
1)常染色体劣性先天性魚鱗癬患者を対象とする病因解明とデータバンク、バイオバンク作成プロジェクト:全国的な常染色体劣性先天性魚鱗癬患者の集積と脂質関連病因遺伝子の同定を行い、多数の常染色体劣性先天性魚鱗癬患者臨床情報と病因の遺伝情報(主に脂質関連遺伝子の病因遺伝子変異)を患者レジストリへ登録、データバンクを作成した。集積した常染色体劣性先天性魚鱗癬患者からのDNA、RNA、皮膚組織等の生体試料のバイオバンクも作成した。
2)常染色体劣性先天性魚鱗癬の病態解明プロジェクト:実際の常染色体劣性先天性魚鱗癬患者の病因遺伝子変異をCRISPR-Cas9によるゲノム編集技術を用いてノックインした真の疾患モデル細胞、モデルマウスの作成を試みた。
3)常染色体劣性先天性魚鱗癬の新規病因治療薬開発プロジェクト:上記の真の常染色体劣性先天性魚鱗癬モデル細胞を用いて、低分子化合物のスクリーニングを試みた。さらに、生物学的製剤を含めた既存薬についてもドラッグ・リポジショニングを目指してスクリーニングを試み、低分子化合物や生物学的製剤の臨床応用の可能性の評価を目指した。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Report

(3 results)
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(24 results)

All 2021 2020 2019 2018 Other

All Journal Article (17 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 16 results,  Open Access: 5 results) Presentation (6 results) (of which Invited: 5 results) Remarks (1 results)

  • [Journal Article] MEDNIK-like syndrome due to compound heterozygous mutations in AP1B1.2021

    • Author(s)
      Ito Y, Takeichi T, Igari S, Mori T, Ono A, Suyama K, Takeuchi S, Muro Y, Ogi T, Hosoya M, Yamamoto T, Akiyama M.
    • Journal Title

      J Eur Acad Dermatol Venereol

      Volume: 35

    • DOI

      10.1111/jdv.17098

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hereditary Mucoepithelial Dysplasia and Autosomal-Dominant IFAP Syndrome Is a Clinical Spectrum Due to SREBF1 Variants2021

    • Author(s)
      Murase Chiaki、Takeichi Takuya、Nomura Toshifumi、Ogi Tomoo、Akiyama Masashi
    • Journal Title

      J Invest Dermatol

      Volume: in press Pages: 1596-1598

    • DOI

      10.1016/j.jid.2020.09.035

    • NAID

      120007175360

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome.2021

    • Author(s)
      Murase C, Takeichi T, Taki T, Yoshikawa T, Suzuki A, Ogi T, Suga Y, Akiyama M.
    • Journal Title

      J Dermatol Sci

      Volume: 102 Pages: 126-129

    • DOI

      10.1016/j.jdermsci.2021.03.003

    • NAID

      120007175359

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Acylceramide is a key player in skin barrier function: insight into the molecular mechanisms of skin barrier formation and ichthyosis pathogenesis.2021

    • Author(s)
      Akiyama M.
    • Journal Title

      FEBS J

      Volume: 288 Pages: 2119-2130

    • DOI

      10.1111/febs.15497

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Recurrent KRT10 variant in ichthyosis with confetti.2020

    • Author(s)
      Takeichi T, Suga Y, Mizuno T, Okuno Y, Ichikawa D, Kono M, Lee JYW, McGrath JA, Akiyama M.
    • Journal Title

      Acta Dermato-Venereol

      Volume: 100

    • DOI

      10.2340/00015555-3570

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mild epidermolytic ichthyosis with palmoplantar keratoderma due to the KRT1 mutation p.lle479Thr.2020

    • Author(s)
      Murase Y, Tanahashi K, Takeichi T, Sugiura K, Aiyama A, Nishida K, Mitsuma T, Akiyama M.
    • Journal Title

      J Dermatol

      Volume: 47

    • DOI

      10.1111/1346-8138.15476

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 【難病研究の進歩】皮膚 先天性魚鱗癬.2020

    • Author(s)
      秋山真志
    • Journal Title

      生体の科学

      Volume: 71 Pages: 526-527

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Reduced stratum corneum acylceramides in autosomal recessive congenital ichthyosis with a NIPAL4 mutation.2020

    • Author(s)
      Murase Y, Takeichi T, Kawamoto A, Tanahashi K, Okuno Y, Takama H, Shimizu E, Ishikawa J, Ogi T, Akiyama M.
    • Journal Title

      J Dermatol Sci

      Volume: 97 Pages: 50-56

    • DOI

      10.1016/j.jdermsci.2019.12.001

    • NAID

      120006849002

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation2020

    • Author(s)
      Takeichi T, Hirabayashi T, Miyasaka Y, Kawamoto A, Okuno Y, Taguchi S, Tanahashi K, Murase C, Takama H, Tanaka K, Boeglin WE, Calcutt MW, Watanabe D, Kono M, Muro Y, Ishikawa J, Ohno T, Brash AR, Akiyama M
    • Journal Title

      J Clin Invest

      Volume: 130 Pages: 890-903

    • DOI

      10.1172/jci130675

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Deep phenotyping of ichthyosis follicularis with atrichia and photophobia syndrome associated with MBTPS2 mutations.2020

    • Author(s)
      Murase C, Takeichi T, Okuno Y, Ikumi K, Morita A, Akiyama M.
    • Journal Title

      J Dermatol

      Volume: 47

    • DOI

      10.1111/1346-8138.15210

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Aberrant CARD14 function might cause defective barrier formation.2019

    • Author(s)
      Murase Y, Takeichi T, Akiyama M.
    • Journal Title

      J Allergy Clin Immunol

      Volume: 143 Pages: 1656-1657

    • DOI

      10.1016/j.jaci.2018.11.044

    • NAID

      120006652417

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Studies on differentiation-dependent expression and activity of distinct transglutaminases by specific substrate peptides using three dimensional reconstituted epidermis.2019

    • Author(s)
      Tanabe Y., Yamane M, Kato M., Teshima H., Kuribayashi M., Tatsukawa H., Takama H., Akiyama M.,  Hitomi K.
    • Journal Title

      The FEBS journal

      Volume: in press Pages: 2536-2548

    • DOI

      10.1111/febs.14832

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] More than keratitis, ichthyosis, and deafness: multisystem effects of lethal GJB2 mutations.2019

    • Author(s)
      Lilly E, Bunick CG, Maley AM, Zhang S, Spraker MK, Theos AJ, Vivar KL, Seminario-Vidal L, Bennett AE, Sidbury R, Ogawa Y, Akiyama M, Binder B, Hadj-Rabia S, Morotti RA, Glusac EJ, Choate KA, Richard G, Milstone LM
    • Journal Title

      J Am Acad Dermatol

      Volume: 80 Pages: 617-625

    • DOI

      10.1016/j.jaad.2018.09.042

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome.2018

    • Author(s)
      Taki T, Takeichi T, Sugiura K, Akiyama M.
    • Journal Title

      Sci Rep.

      Volume: 8 Pages: 12824-12824

    • DOI

      10.1038/s41598-018-30757-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cross-sectional survey on disease severity in Japanese patients with harlequin ichthyosis/ichthyosis: Syndromic forms and quality-of-life analysis in a subgroup.2018

    • Author(s)
      Murase C, Takeichi T, Shibata A, Nakatochi M, Kinoshita F, Kubo A, Nakajima K, Ishii N, Amano H, Masuda K, Kawakami H, Kanekura T, Washio K, Asano M, Teramura K, Akasaka E, Tohyama M, Hatano Y, Ochiai T, Moriwaki S, Sato T, Ishida-Yamamoto A, Seishima M, Kurosawa M, Ikeda S, Akiyama M.
    • Journal Title

      J Dermatol Sci

      Volume: 92 Pages: 127-133

    • DOI

      10.1016/j.jdermsci.2018.08.008

    • NAID

      120006623824

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency.2018

    • Author(s)
      Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency.
    • Journal Title

      J Lipid Res

      Volume: 59 Pages: 2413-1420

    • DOI

      10.1194/jlr.p087536

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sterol profiles are valuable biomarkers for phenotype expression of Conradi-Hünermann-Happle syndrome with EBP mutations.2018

    • Author(s)
      Takeichi T, Honda A, Okuno Y, Kojima D, Kono M, Nakamura Y, Tohyama M, Tanaka T, Aoyama Y, Akiyama M.
    • Journal Title

      Br J Dermatol

      Volume: 179 Pages: 1186-1188

    • DOI

      10.1111/bjd.16823

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] Dupilumabが奏効したNetherton症候群の一例.2021

    • Author(s)
      秋山真志、村瀬千晶、滝 奉樹、武市拓也、須賀 康.
    • Organizer
      第295回日本皮膚科学会東海地方会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 角化症を科学する2020

    • Author(s)
      秋山真志
    • Organizer
      第71回日本皮膚科学会中部支部学術大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 遺伝性角化症かも?と思ったら2019

    • Author(s)
      秋山真志
    • Organizer
      第35回日本臨床皮膚科医会総会・学術大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 表皮脂質の機能障害による疾患群:魚鱗癬と魚鱗癬症候群.2019

    • Author(s)
      秋山真志
    • Organizer
      第61回日本脂質生化学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 表皮脂質が担う皮膚バリア機能2018

    • Author(s)
      秋山真志
    • Organizer
      第82回日本皮膚科学会東京支部学術大会(教育講演)(国内学会)
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 魚鱗癬・魚鱗癬症候群の病態から解き明かされる、表皮バリアの形成機構2018

    • Author(s)
      秋山真志
    • Organizer
      第91回日本生化学会大会(シンポジウム)(国内学会)
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Remarks] 名古屋大学大学院医学系研究科皮膚科学分野のホームページ

    • URL

      https://www.med.nagoya-u.ac.jp/derma/

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report 2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-12-28  

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