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細胞老化へ向かう代謝アダプテーションのエピゲノムからの探索

Publicly Offered Research

Project AreaTransomic Analysis of Metabolic Adaptation
Project/Area Number 18H04795
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Research InstitutionTohoku University

Principal Investigator

中山 啓子  東北大学, 医学系研究科, 教授 (60294972)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
KeywordsRASシグナル / 細胞老化 / トランスオミクス解析 / エピゲノム制御 / ヒストンH3 Lys27メチル化
Outline of Annual Research Achievements

RASシグナルに応答して変化するヒストン修飾を明らかにすることが本研究の目的である。哺乳類培養細胞であるヒト由来正常線維芽細胞(TIG-3)にRAS遺伝子を導入してRASシグナルを誘導後、35日間にわたりRNAとクロマチンを経時的に回収し、注目している遺伝子群の転写量とエピゲノムの変化について、解析を行った。
さらにプロテオミクス技術を用いて、転写の変化がタンパク質の変化とどの様にリンクするのかその評価を行った。その際に、RASと同様に老化表現系を誘導するその他の2種類の刺激での測定も行った。
具体的には、複製老化、RASシグナル活性化によるがん遺伝子誘発性細胞老化、酸化ストレス誘発性細胞老化の3種類の老化である。これらは、増殖を停止し特徴的な細胞形態を示す。
この様な老化という共通の表現型を持つ細胞にも関わらず、プロテオミクス解析によって共通して増加または減少している酵素は少なく、それぞれの入力シグナルによって変動している酵素が多いことが判明した。そこで、これらの共通部分どのような代謝経路を制御しているのかを探索を行った。また、非共通部分がこの老化表現型に果たす役割についても検討を行った。
一方で、トランスクリプトームの変動と比較する事で、mRNA量とタンパク質量との相関を調べ、タンパク質発現パターンの変動を誘導しているメカニズムが、転写レベルで生じているのか、翻訳後に起こる現象なのかを確認し、それらを引き起こす分子機構の解明を試みている。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (23 results)

All 2021 2020 2019 2018 Other

All Journal Article (15 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 15 results,  Open Access: 10 results) Presentation (6 results) Remarks (2 results)

  • [Journal Article] Study Profile of the Tohoku Medical Megabank Community-Based Cohort Study2021

    • Author(s)
      Hozawa A, Tanno K, Nakaya N, Nakamura T, Tsuchiya N, Hirata T, Narita A, Kogure M, Nochioka K, Sasaki R, Takanashi N, Otsuka K, Sakata K, Kuriyama S, Kikuya M, 13名略, Kobayashi T, 53名略, Yamamoto M.
    • Journal Title

      Journal of Epidemiology

      Volume: 31 Issue: 1 Pages: 65-76

    • DOI

      10.2188/jea.JE20190271

    • NAID

      130007966030

    • ISSN
      0917-5040, 1349-9092
    • Year and Date
      2021-01-05
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice2020

    • Author(s)
      Wada Yoichi、Kikuchi Atsuo、Kaga Akimune、Shimizu Naoki、Ito Junya、Onuma Ryo、Fujishima Fumiyoshi、Totsune Eriko、Sato Ryo、Niihori Tetsuya、Shirota Matsuyuki、Funayama Ryo、Sato Kota、Nakazawa Toru、Nakayama Keiko、Aoki Yoko、Aiba Setsuya、Nakagawa Kiyotaka、Kure Shigeo
    • Journal Title

      PLOS Genetics

      Volume: 16 Issue: 2 Pages: e1008628-e1008628

    • DOI

      10.1371/journal.pgen.1008628

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis.2020

    • Author(s)
      Masamune A, Kotani H, Sorgel FL, Chen JM, Hamada S, Sakaguchi R, Masson E, Nakano E, et al.
    • Journal Title

      Gastroenterology

      Volume: - Issue: 6 Pages: 1626-1641

    • DOI

      10.1053/j.gastro.2020.01.005

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] BACH1 Promotes Pancreatic Cancer Metastasis by Repressing Epithelial Genes and Enhancing Epithelial-Mesenchymal Transition2020

    • Author(s)
      Sato Masaki、Matsumoto Mitsuyo、Saiki Yuriko、Alam Mahabub、Nishizawa Hironari、Rokugo Masahiro、Brydun Andrey、Yamada Shinji、Kaneko Mika K.、Funayama Ryo、Ito Mamoru、Kato Yukinari、Nakayama Keiko、Unno Michiaki、Igarashi Kazuhiko
    • Journal Title

      Cancer Research

      Volume: 80 Issue: 6 Pages: 1279-1292

    • DOI

      10.1158/0008-5472.can-18-4099

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Knockout Mouse Models Provide Insight into the Biological Functions of CRL1 Components.2020

    • Author(s)
      Nakagawa T, Nakayama K, Nakayama KI.
    • Journal Title

      Adv Exp Med Biol.

      Volume: 1217 Pages: 147-171

    • DOI

      10.1007/978-981-15-1025-0_10

    • ISBN
      9789811510243, 9789811510250
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): Rationale, progress and perspective2020

    • Author(s)
      Kuriyama S, Metoki H, Kikuya M, Obara T, Ishikuro M, Yamanaka C, Nagai M, Matsubara H, Kobayashi T, 57名略, Yamamoto M.
    • Journal Title

      Int J Epidemiol.

      Volume: 49 Issue: 1 Pages: 18

    • DOI

      10.1093/ije/dyz169

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome2019

    • Author(s)
      Niitsuma Sou、Kudo Hiroki、Kikuchi Atsuo、Hayashi Takaya、Kumakura Satoshi、Kobayashi Shuhei、Okuyama Yuko、Kumagai Naonori、Niihori Tetsuya、Aoki Yoko、So Takanori、Funayama Ryo、Nakayama Keiko、Shirota Matsuyuki、Kondo Shuji、Kagami Shoji、Tsukaguchi Hiroyasu、Iijima Kazumoto、Kure Shigeo、Ishii Naoto
    • Journal Title

      International Immunology

      Volume: 32 Issue: 4 Pages: 283-292

    • DOI

      10.1093/intimm/dxz081

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity.2019

    • Author(s)
      Yu Y, Nakagawa T, Morohoshi A, Nakagawa M, Ishida N, Suzuki N, Aoki M, Nakayama K.
    • Journal Title

      Hum Mol Genet

      Volume: 28 Issue: 20 Pages: 3486-3497

    • DOI

      10.1093/hmg/ddz119

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Detection of NRAS mutation in cell-free DNA biological fluids from patients with kaposiform lymphangiomatosis2019

    • Author(s)
      Ozeki Michio、Aoki Yoko、Nozawa Akifumi、Yasue Shiho、Endo Saori、Hori Yumiko、Matsuoka Kentaro、Niihori Tetsuya、Funayama Ryo、Shirota Matsuyuki、Nakayama Keiko、Fukao Toshiyuki
    • Journal Title

      Orphanet Journal of Rare Diseases

      Volume: 14 Issue: 1 Pages: 215-215

    • DOI

      10.1186/s13023-019-1191-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cancer‐associated fibroblasts secrete Wnt2 to promote cancer progression in colorectal cancer2019

    • Author(s)
      Aizawa Takashi、Karasawa Hideaki、Funayama Ryo、Shirota Matsuyuki、Suzuki Takashi、Maeda Shimpei、Suzuki Hideyuki、Yamamura Akihiro、Naitoh Takeshi、Nakayama Keiko、Unno Michiaki
    • Journal Title

      Cancer Medicine

      Volume: 8 Issue: 14 Pages: 6370-6382

    • DOI

      10.1002/cam4.2523

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons.2019

    • Author(s)
      Akiyama T, Suzuki N, Ishikawa M, Fujimori K, Sone T, Kawada J, Funayama R, Fujishima F, Mitsuzawa S, Ikeda K, Ono H, Shijo T, Osana S, Shirota M, Nakagawa T, et al.
    • Journal Title

      EBioMedicine

      Volume: 45 Pages: 362-378

    • DOI

      10.1016/j.ebiom.2019.06.013

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Germline-Activating RRAS2 Mutations Cause Noonan Syndrome2019

    • Author(s)
      Niihori Tetsuya、Nagai Koki、Fujita Atsushi、Ohashi Hirofumi、Okamoto Nobuhiko、Okada Satoshi、Harada Atsuko、Kihara Hirotaka、Arbogast Thomas、Funayama Ryo、Shirota Matsuyuki、Nakayama Keiko、Abe Taiki、Inoue Shin-ichi、Tsai I-Chun、Matsumoto Naomichi、Davis Erica E.、Katsanis Nicholas、Aoki Yoko
    • Journal Title

      The American Journal of Human Genetics

      Volume: 104 Issue: 6 Pages: 1233-1240

    • DOI

      10.1016/j.ajhg.2019.04.014

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Recurrent de novo MAPK8IP3 variants cause neurological phenotypes2019

    • Author(s)
      Iwasawa Shinya、Yanagi Kumiko、Kikuchi Atsuo、Kobayashi Yasuko、Haginoya Kazuhiro、Matsumoto Hiroshi、Kurosawa Kenji、Ochiai Masayuki、Sakai Yasunari、Fujita Atsushi、Miyake Noriko、Niihori Tetsuya、ら
    • Journal Title

      Annals of Neurology

      Volume: - Issue: 6 Pages: 927-933

    • DOI

      10.1002/ana.25481

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The ubiquitin ligase subunit β-TrCP in Sertoli cells is essential for spermatogenesis in mice.2019

    • Author(s)
      Morohoshi, A., Nakagawa, T., Nakano, S., Nagasawa, Y., Nakayama, K.
    • Journal Title

      Dev Biol.

      Volume: 445 Issue: 2 Pages: 178-188

    • DOI

      10.1016/j.ydbio.2018.10.023

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Peroxisome biogenesis deficiency attenuates the BDNF-TrkB pathway-mediated development of the cerebellum2018

    • Author(s)
      Abe Yuichi、Honsho Masanori、Itoh Ryota、Kawaguchi Ryoko、Fujitani Masashi、Fujiwara Kazushirou、Hirokane Masaaki、Matsuzaki Takashi、Nakayama Keiko、Ohgi Ryohei、Marutani Toshihiro、Nakayama Keiichi I、Yamashita Toshihide、Fujiki Yukio
    • Journal Title

      Life Science Alliance

      Volume: 1 Issue: 6 Pages: 1-17

    • DOI

      10.26508/lsa.201800062

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 蛋白分解異常による新規筋萎縮性側索硬化症の発症機構2019

    • Author(s)
      渡辺 靖章, 中川 直, 鈴木 直輝, 割田 仁, 中山 啓子, 青木 正志
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 知的障害・自閉症関連因子SETD5によるrDNAのエピジェネティック制御2019

    • Author(s)
      中川直,中山啓子
    • Organizer
      第42回分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Alternative Splicing of FBLN2 generates two proteins with different N-linked glycosylation patterns2019

    • Author(s)
      Wei Chen,Ryo Funayama, Keiko Nakayama
    • Organizer
      第42回分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ユビキチン化によるFACT複合体の機能制御2018

    • Author(s)
      中川直、諸星茜、中山啓子
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 大腸がんにおけるFibulin2スプライスバリアントの役割2018

    • Author(s)
      舟山亮、遠山慎吾、高唯真、中山啓子
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Mutation of cyclin F may contribute to Amyotrophic Lateral Sclerosis pathogensis by affecting VCP ATPase activity2018

    • Author(s)
      Yujao Yu, Akane Morohoshi, Tadashi Nakagawa, Keiko Nakayama
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Remarks] 東北大学大学院医学系研究科附属創生応用医学研究センターがん医学コアセンター細胞増殖制御分野

    • URL

      http://www.devgen.med.tohoku.ac.jp/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 東北大学医学系研究科細胞増殖制御分野HP

    • URL

      http://www.devgen.med.tohoku.ac.jp/

    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2021-01-27  

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