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Elucidation of etiology and phenotypic control in a porcine autosomal dominant genetic disease model

Research Project

Project/Area Number 15H02480
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Integrative animal science
Research InstitutionMeiji University

Principal Investigator

Nagashima Hiroshi  明治大学, 農学部, 専任教授 (50318664)

Co-Investigator(Kenkyū-buntansha) 大鐘 潤  明治大学, 農学部, 専任准教授 (50313078)
Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥41,730,000 (Direct Cost: ¥32,100,000、Indirect Cost: ¥9,630,000)
Fiscal Year 2018: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000)
Fiscal Year 2017: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000)
Fiscal Year 2016: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000)
Fiscal Year 2015: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
Keywordsブタ / 遺伝子改変動物 / 常染色体優性遺伝病 / ハプロ不全 / マルファン症候群モデル / エピジェネティクス / CpG shore / メチル化修飾 / 発生工学 / 遺伝学 / 応用動物 / ゲノム
Outline of Final Research Achievements

Marfan syndrome (MFS) is an autosomal dominant genetic disease. We established a porcine model for MFS by introducing a mutation (Glu433AsnfsX98) in the Fibrillin1 (FBN1) gene. We also identified a single nucleotide polymorphism (SNP) in FBN1 promotor CpG shore in a pig. Using the offspring (F1) obtained by mating of MFS females and a SNP-identified male, relationship between the methylation status of FBN1 CpG shore and the expression level of FBN1 was identified. Our results suggested that epigenetic modification of the responsible gene expression is involved in the etiology of MFS exhibiting haploinsufficiency.

Academic Significance and Societal Importance of the Research Achievements

常染色体優性遺伝病において、正常アリルのみからの発現量では遺伝子産物量が不足するために発症するものはハプロ不全と呼ばれる。ハプロ不全では原因遺伝子の塩基配列のみからは十分説明できないため、発症の有無に浸透度、発症組織の違いなどに表現度といった遺伝学用語を当てはめて、統計的な確率論として議論してきた。本研究では、ハプロ不全性の優性遺伝病の発症機序にエピジェネティクスからアプローチしている。エピジェネティクス研究によってハプロ不全性優性遺伝病の病態発現の制御が解明できれば、疾患モデルブタを用いた前臨床的研究や創薬研究が飛躍的に発展することが期待できる。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (50 results)

All 2019 2018 2017 2016 2015 Other

All Int'l Joint Research (2 results) Journal Article (7 results) (of which Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (39 results) (of which Int'l Joint Research: 10 results,  Invited: 12 results) Book (2 results)

  • [Int'l Joint Research] Cincinnati Children’s Medical Center/Vanderbilt University(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Cincinnati Children’s Medical Center(米国)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] ゲノム編集と実験動物(IV)-ブタのゲノム編集2017

    • Author(s)
      1.渡邊將人
    • Journal Title

      LABIO21

      Volume: 70 Pages: 5-8

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Evidence of exposure to chemicals and heavy metals during pregnancy in Japanese women2017

    • Author(s)
      Maekawa Ryo、Ito Rie、Iwasaki Yusuke、Saito Koichi、Akutsu Kazuhiko、Takatori Satoshi、Ishii Rie、Kondo Fumio、Arai Yoshikazu、Ohgane Jun、Shiota Kunio、Makino Tsunehisa、Sugino Norihiro
    • Journal Title

      Reproductive Medicine and Biology

      Volume: 16 Issue: 4 Pages: 337-348

    • DOI

      10.1002/rmb2.12049

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of DNA methylation patterns of the <i>Fibrillin1</i> (<i>FBN1</i>) gene in porcine embryos and tissues2017

    • Author(s)
      Arai Y, Umeyama K, Takeuchi K, Okazaki N, Hichiwa N, Yashima S, Nakano K, Nagashima H, Ohgane J
    • Journal Title

      Journal of Reproduction and Development

      Volume: 63 Issue: 2 Pages: 157-165

    • DOI

      10.1262/jrd.2016-158

    • NAID

      130007314629

    • ISSN
      0916-8818, 1348-4400
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Involvement of DNA methylation in regulating rat <i>Prop1</i> gene expression during pituitary organogenesis2017

    • Author(s)
      Nishihara H, Yoshida S, Kanno N, Nishimura N, Ueharu H, Ohgane J, Kato T, Kato Y
    • Journal Title

      Journal of Reproduction and Development

      Volume: 63 Issue: 1 Pages: 37-44

    • DOI

      10.1262/jrd.2016-102

    • NAID

      130005332293

    • ISSN
      0916-8818, 1348-4400
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Generation of heterozygous fibrillin-1 mutant cloned pigs from genome-edited foetal fibroblasts2016

    • Author(s)
      Umeyama K, Watanabe K, Watanabe M, Horiuchi K, Nakano K, Kitashiro M, Matsunari H, Kimura T, Arima Y, Sampetrean O, Nagaya M, Saito M, Saya H, Kosaki K, Nagashima H & Matsumoto M
    • Journal Title

      Sci Rep.

      Volume: 6:24413 Issue: 1 Pages: 1-4

    • DOI

      10.1038/srep24413

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ultra-Deep Bisulfite Sequencing to Detect Specific DNA Methylation Patterns of Minor Cell Types in Heterogeneous Cell Populations: An Example of the Pituitary Tissue2016

    • Author(s)
      Arai Y, Fukukawa H, Atozi T, Matsumoto S, Hanazono Y, Nagashima H, and Ohgane J.
    • Journal Title

      PLoS One

      Volume: 11 Issue: 1 Pages: e0146498-e0146498

    • DOI

      10.1371/journal.pone.0146498

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ハプロ不全優性遺伝病発症の新たな視点:分子メカニズムとしてエピジェネティクスが関与する可能性2016

    • Author(s)
      竹内健太、牧野智宏、新井良和、大鐘潤
    • Journal Title

      明治大学農学部研究報告

      Volume: 65 Pages: 96-103

    • NAID

      120005941792

    • Related Report
      2015 Annual Research Report
  • [Presentation] 変異FBN1遺伝子ブタにおける肢指間節および心臓血管異常2019

    • Author(s)
      梅山一大、飛田公理、中野和明、武藤智之、山田猛、戎谷力也、松成ひとみ、渡邊將人、 長嶋比呂志
    • Organizer
      第66回日本実験動物学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 変異FBN1遺伝子ブタの表現型 ―Marfan症候群病態との比較―2018

    • Author(s)
      梅山一大
    • Organizer
      第6回日本先進医工学ブタ研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ゲノム編集による単一遺伝子疾患モデルブタの開発と現状2018

    • Author(s)
      渡邊將人
    • Organizer
      第6回日本先進医工学ブタ研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ゲノム編集による遺伝子改変ブタの作出とその利用2018

    • Author(s)
      渡邊將人
    • Organizer
      日本生薬学会第65回年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Comparative analysis of mouse and pig models of Marfan syndrome unveils an inflammatory micro-environment and macrophages as novel features of myxomatous valve disease2018

    • Author(s)
      A. J. Kim, K. Umeyama, A. Hulin, R. J. Vagnozzi, E. A. Green, H. Nagashima, K. E. Yutzey
    • Organizer
      5th Mid-America Valve Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] マルファン症候群モデルブタの病態発現制御2018

    • Author(s)
      武藤智之,梅山一大,内倉鮎子,岡本一駿,徳山雄紀,中野和明,松成ひとみ,渡邊將人, 長屋昌樹,長嶋比呂志
    • Organizer
      第111回日本繁殖生物学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アリルごとのDNAメチル化に着目したハプロ不全優性遺伝病の発症機序解明に向けた新たな試み:ブタフィブリリン1(FBN1)を例として2018

    • Author(s)
      新井良和, 梅山一大, 岡崎なつみ, 隠地健斗, 福川斐昭, 高澤建, 西野光一郎, 長嶋比呂志, 大鐘潤
    • Organizer
      第111回日本繁殖生物学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Immunogenic extracellular matrix remodeling and macrophage contributions to heart valve disease in genetic mouse and pig models of Marfan syndrome2018

    • Author(s)
      A. J. Kim, A. Hulin, K. Umeyama, R. J. Vagnozzi1, H. Nagashima, K. E. Yutzey
    • Organizer
      33rd National MD/PhD Student Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] DNA methylation as an epigenetic modifier of the FBN1 transcription2018

    • Author(s)
      Ohgane J., Arai Y., Takeuchi K., Okazaki N., Nakano K., Matsunari H., Watanabe M., Umeyama K., Nagashima H
    • Organizer
      10th International Research Symposium on Marfan Syndrome and Related Disorders
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Phenotype of homozygouse fibrillin-1 (FBN1) mutant pigs2018

    • Author(s)
      Umeyama K., Arai Y., Nakano K., Uchikura A., Watanabe M., Matsunari H., Saito M., Saya H., Matsumoto M., Nagaya M., Ohgane J., Nagashima H
    • Organizer
      10th International Research Symposium on Marfan Syndrome and Related Disorders
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A nobel large animal disease model of marfan syndrome: FBN1 edited pigs2018

    • Author(s)
      Roberts A., Umeyama K., Watanabe M., Matsunari H., Nakano K., Morooka A., Nagashima H
    • Organizer
      10th International Research Symposium on Marfan Syndrome and Related Disorders
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 遺伝子改変ブタの作出とその利用2018

    • Author(s)
      渡邊將人
    • Organizer
      第124回日本畜産学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] DNAメチル化によるブタMSTN遺伝子の組織特異的発現調節機構の解2018

    • Author(s)
      隠地健斗、新井良和、長嶋比呂志、大鐘潤
    • Organizer
      第124回 日本畜産学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ブタにおけるOTC欠損症原因遺伝子のエピジェネティック解析2018

    • Author(s)
      茂田遼平、新井良和、松成ひとみ、長嶋比呂志、大鐘潤
    • Organizer
      第124回 日本畜産学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] アリルごとのDNAメチル化状態に注目したエピジェネティクス解析の新たな試み2017

    • Author(s)
      大鐘潤、新井良和
    • Organizer
      2017年日本農芸化学会年会シンポジウム
    • Place of Presentation
      京都
    • Year and Date
      2017-03-17
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Phenotypic variation in the cloned pigs with heterozygous fibrillin-1 mutation2017

    • Author(s)
      Umeyama K, Arai Y, Nakano K, Fukuda T, Umeki I, Uchikura A, Kasai Y, Matsunari H, Nagaya M, Watanabe M, Ohgane J and Nagashima H
    • Organizer
      4th World Congress of Reproductive Biology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] マルファン症候群モデルブタの開発2017

    • Author(s)
      長嶋比呂志
    • Organizer
      第64回日本実験動物学会総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 変異型fibrillin-1遺伝子を有するブタの上行大動脈の病理解析2016

    • Author(s)
      梅山一大, 新井良和, 中野和明, 内倉鮎子, 渡邊将人, 松成ひとみ, 齋藤正寛, 木村徳宏, 渡邊航太, 堀内圭輔, 北城雅照, 有馬好美, サンペトラオルテア, 小崎健次郎, 佐谷秀行, 松本守雄, 長屋昌樹, 大鐘潤, 長嶋比呂志
    • Organizer
      第57回日本脈管学会総会
    • Place of Presentation
      奈良
    • Year and Date
      2016-10-13
    • Related Report
      2016 Annual Research Report
  • [Presentation] 疾患モデルブタ・ミニブタ開発の現状と展望2016

    • Author(s)
      長嶋比呂志
    • Organizer
      第4回日本先進医工学ブタ研究会
    • Place of Presentation
      三島
    • Year and Date
      2016-10-06
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] FBN1遺伝子変異を有するマルファン症候群モデルブタ由来の脱分化脂肪細胞株(DFAT)樹立と特性解析2016

    • Author(s)
      酒井成貴, 信末博行, 有馬好美, 梅山一大, 長嶋比呂志, 佐谷秀行, 貴志和生
    • Organizer
      第25回日本形成外科学会基礎学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2016-09-15
    • Related Report
      2016 Annual Research Report
  • [Presentation] ハプロ不全優成遺伝病の発生機序解明に向けた新たなアプローチ:ブタフィブリリン1(FBN1)2016

    • Author(s)
      新井良和, 梅山一大, 竹内健太, 八島紗耶香, 中野和明, 長嶋比呂志, 大鐘潤
    • Organizer
      第109回日本繁殖生物学会
    • Place of Presentation
      相模原
    • Year and Date
      2016-09-12
    • Related Report
      2016 Annual Research Report
  • [Presentation] ブタにおけるゲノム編集技術を用いた遺伝子ノックアウト2016

    • Author(s)
      渡邊将人, 松成ひとみ, 中野和明, 梅山一大, 高柳就子, 長屋昌樹, 宮川周士, 花園豊, 中内啓光, 長嶋比呂志
    • Organizer
      日本ゲノム編集学会第1回大会
    • Place of Presentation
      広島
    • Year and Date
      2016-09-07
    • Related Report
      2016 Annual Research Report
  • [Presentation] ホモ変異型fibrillin-1遺伝子を有するブタの表現型2016

    • Author(s)
      梅山一大, 新井良和, 中野和明, 内倉鮎子, 渡邊將人, 松成ひとみ, 齋藤正寛, 佐谷秀行, 松本守雄, 長屋昌樹, 大鐘潤, 長嶋比呂志
    • Organizer
      第48回日本結合組織学会学術大会
    • Place of Presentation
      長崎
    • Year and Date
      2016-06-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] 動物のゲノム編集とその医学応用2016

    • Author(s)
      長嶋比呂志
    • Organizer
      日本ビタミン学会第68回大会
    • Place of Presentation
      富山
    • Year and Date
      2016-06-17
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Combining breeding and advanced reproduction techniques for regenerative medicine2016

    • Author(s)
      Nagashima H
    • Organizer
      Plant and Animal Genome Asia 2016
    • Place of Presentation
      Singapore, Singapore
    • Year and Date
      2016-06-06
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 体細胞核移植で継代されたクローンブタでのゲノムワイドDNAメチル化解析2016

    • Author(s)
      新井良和、福川斐昭、飛知和尚美、松成ひとみ、長嶋比呂志、大鐘潤
    • Organizer
      第10回日本エピジェネティクス研究会
    • Place of Presentation
      大阪
    • Year and Date
      2016-05-19
    • Related Report
      2016 Annual Research Report
  • [Presentation] ゲノム編集ブタにおけるヘテロ変異fibrillin-1遺伝子の後代への伝達と発現2016

    • Author(s)
      梅山一大, 渡辺航太, 渡邊将人, 堀内圭輔, 中野和明, 北城雅照, 松成ひとみ, 長屋昌樹, 松本守雄, 長嶋比呂志
    • Organizer
      第63回日本実験動物学会総会
    • Place of Presentation
      川崎
    • Year and Date
      2016-05-18
    • Related Report
      2016 Annual Research Report
  • [Presentation] クローン動物と遺伝子改変2016

    • Author(s)
      長嶋比呂志
    • Organizer
      染色体学会第67回年会(市民講座)
    • Place of Presentation
      東京
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Pig model of rare monogenic diseases2016

    • Author(s)
      Nagashima H
    • Organizer
      18th International Congress of Animal Reproduction, SALAAM-Workshop
    • Place of Presentation
      Tours, France
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 人工ヌクレアーゼを用いた遺伝子ノックアウト細胞の樹立およびブタの作出効率2015

    • Author(s)
      渡邊將人、松成ひとみ、中野和明、梅山一大、長屋昌樹、宮川周士、花園 豊、中内啓光、長嶋比呂志
    • Organizer
      第38回日本分子生物学会年会
    • Place of Presentation
      兵庫県神戸市
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] Zinc finger nucleaseによるfibrillin 1遺伝子ノックアウトブタの作出 -側弯症モデルの開発をめざして2015

    • Author(s)
      渡辺航太、堀内圭輔、梅山一大、長嶋比呂志、中村雅也、松本守雄
    • Organizer
      第30回日本整形外科学会基礎学術集会
    • Place of Presentation
      富山県富山市
    • Year and Date
      2015-10-22
    • Related Report
      2015 Annual Research Report
  • [Presentation] ゲノム編集によるブタ遺伝子改変2015

    • Author(s)
      渡邊將人
    • Organizer
      第3回日本先進医工学ブタ研究会
    • Place of Presentation
      東京都千代田区
    • Year and Date
      2015-10-16
    • Related Report
      2015 Annual Research Report
  • [Presentation] Generation of FBN1 gene knockout pig model for Marfan syndrome2015

    • Author(s)
      Morio Matsumoto, Kota Watanabe, Keisuke Horiuchi, Kazuhiro Umeyama, Hiroshi Nagashima
    • Organizer
      Scoliosis Research Society presents 50th Annual Meeting & Course
    • Place of Presentation
      Minneapolis, Minnesota, USA
    • Year and Date
      2015-09-30
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Fibrillin-1遺伝子ノックアウトによるMarfan症候群モデルブタの開発2015

    • Author(s)
      笠井悠里,梅山一大,渡邊將人,中野和明,松成ひとみ,内倉鮎子, 武石透輝,畑江将太,浅野吉則,長屋昌樹,渡辺航太, 堀内圭輔, 松本守雄,長嶋比呂志
    • Organizer
      第108回日本繁殖生物学会大会
    • Place of Presentation
      宮崎県宮崎市
    • Year and Date
      2015-09-17
    • Related Report
      2015 Annual Research Report
  • [Presentation] 体細胞連続核移植で作出されたクローンブタでのエピジェネティック解析:Human BeadChipを用いたゲノムワイドDNAメチル化解析の試み2015

    • Author(s)
      新井良和、阿閉貴紀、福川斐昭、齊藤経、竹内健太、松成ひとみ、長嶋比呂志、大鐘潤
    • Organizer
      第108回日本繁殖生物学会大会
    • Place of Presentation
      宮崎県宮崎市
    • Year and Date
      2015-09-17
    • Related Report
      2015 Annual Research Report
  • [Presentation] ブタにおけるゲノム編集技術の利用2015

    • Author(s)
      渡邊將人
    • Organizer
      第28回日本動物細胞工学会2015年度大会
    • Place of Presentation
      宮城県仙台市
    • Year and Date
      2015-07-09
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] ゲノム編集を用いた遺伝子ノックアウトクローンブタの作出効率2015

    • Author(s)
      渡邊將人, 松成ひとみ, 中野和明, 梅山一大, 長屋昌樹, 宮川周士、花園 豊、中内啓光、長嶋比呂志
    • Organizer
      第28回日本動物細胞工学会2015年度大会
    • Place of Presentation
      宮城県仙台市
    • Year and Date
      2015-07-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] Generation of FBN1 Gene Knockout Pig Model for Marfan Syndrome2015

    • Author(s)
      Morio Matsumoto, Kota Watanabe, Keisuke Horiuchi, Kazuhiro Umeyama, Hiroshi Nagashima
    • Organizer
      22nd International Meeting on Advanced Spine Techniques
    • Place of Presentation
      Kuala Lumpur, Malaysia
    • Year and Date
      2015-07-08
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Zinc finger nucleaseによるfibrillin 1遺伝子ヘテロノックアウトクローンブタの作出2015

    • Author(s)
      梅山一大、渡辺航太、渡邊將人、堀内圭輔、中野和明、松成ひとみ、長屋昌樹、松本守雄、長嶋比呂志
    • Organizer
      第47回日本結合組織学会学術大会
    • Place of Presentation
      東京都港区
    • Year and Date
      2015-05-15
    • Related Report
      2015 Annual Research Report
  • [Book] Genome editing of pig. In: Genome Editing in Animals: Methods and Protocols (Methods in Molecular Biology) Vol.1630 p121-1392017

    • Author(s)
      Watanabe M, Nagashima H
    • Total Pages
      256
    • Publisher
      Humana Press
    • ISBN
      9781493971275
    • Related Report
      2017 Annual Research Report
  • [Book] 実験医学増刊Vol.34 No.20 All Aboutゲノム編集“革命的技術"はいかにして私たちの研究・医療・産業を変えるのか?2016

    • Author(s)
      渡邊將人, 長嶋比呂志
    • Total Pages
      234
    • Publisher
      羊土社
    • Related Report
      2016 Annual Research Report

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Published: 2015-04-16   Modified: 2020-03-30  

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