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Elucidation of the molecular pathogenesis of genetic disorders caused by defects in DNA damage response using deep proteomic analysis

Research Project

Project/Area Number 18H03372
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 63020:Radiation influence-related
Research InstitutionNagoya University

Principal Investigator

Oka Yasuyoshi  名古屋大学, 環境医学研究所, 講師 (60762383)

Co-Investigator(Kenkyū-buntansha) 荻 朋男  名古屋大学, 環境医学研究所, 教授 (80508317)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2018: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
KeywordsDNA損傷応答システム / ゲノム不安定性 / 遺伝性疾患 / プロテオーム解析 / 疾患ゲノム解析 / マルチオミクス解析
Outline of Final Research Achievements

DNA damage response is prerequisite for the maintenance of genomic stability. Mutations in genes encoding many components of DNA damage response can result in a number of genetic disorders. Recent extensive studies using NGS analysis identify pathogenic mutations in patients with genomic instability. Because the average healthy person has dozens of genetic variants predicted to severely disrupt protein-coding genes, known as loss-of-function variants, and WES is not able to detect chromosomal translocations, large chromosomal deletions and non-canonical splicing mutations, it is difficult to narrow down and identify pathogenic mutations from patients with extremely rare genetic diseases using only NGS technologies. Using deep proteome analysis, we found the novel disease-causing mutation in the RNASEH2B gene from the patient with microcephaly, cerebral atrophy, and basal ganglia calcification, who was undiagnosed using a WES analysis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、全エキソーム解析のみでは疾患発症因子の同定に至らなかった症例について、プロテオーム解析を実施することで、原因因子を特定することが可能となった。全エキソーム解析に加えて、全ゲノム解析、RNAシーケンス解析、本研究で実施したプロテオーム解析を組み合わせた、マルチオミクス解析を実施することにより、診断率の向上ならびに未診断遺伝性疾患の病態解明へと繋がることが期待される。

Report

(4 results)
  • 2021 Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (42 results)

All 2021 2020 2019 2018 Other

All Journal Article (22 results) (of which Int'l Joint Research: 12 results,  Peer Reviewed: 22 results,  Open Access: 13 results) Presentation (16 results) (of which Int'l Joint Research: 4 results,  Invited: 6 results) Remarks (2 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] A novel missense variant in CUL3 shows altered binding ability to BTB-adaptor proteins leading to diverse phenotypes of CUL3-related disorders2021

    • Author(s)
      Kato Kohji、Miya Fuyuki、Oka Yasuyoshi、Mizuno Seiji、Saitoh Shinji
    • Journal Title

      Journal of Human Genetics

      Volume: 66 Issue: 5 Pages: 491-498

    • DOI

      10.1038/s10038-020-00868-9

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model.2021

    • Author(s)
      Yoshioka N, Tanaka M, Ochi K, Watanabe A, Ono K, Sawada M, Ogi T, Itoh M, Ito A, Shiraki Y, Enomoto A, Ishigami M, Fujishiro M, Ogawa Y, Suganami T.
    • Journal Title

      Biomed Pharmacother

      Volume: 140 Pages: 111738-111738

    • DOI

      10.1016/j.biopha.2021.111738

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dealing with transcription-blocking DNA damage: Repair mechanisms, RNA polymerase II processing and human disorders2021

    • Author(s)
      Jia Nan、Guo Chaowan、Nakazawa Yuka、van den Heuvel Diana、Luijsterburg Martijn S.、Ogi Tomoo
    • Journal Title

      DNA Repair

      Volume: 106 Pages: 103192-103192

    • DOI

      10.1016/j.dnarep.2021.103192

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation2021

    • Author(s)
      van der Weegen Yana、(著者19人)、Ogi Tomoo、Wolthuis Rob M. F.、Luijsterburg Martijn S.
    • Journal Title

      Nature Cell Biology

      Volume: 23 Issue: 6 Pages: 595-607

    • DOI

      10.1038/s41556-021-00688-9

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder2021

    • Author(s)
      Jiang Wenjun、Jia Nan、Guo Chaowan、Wen Juan、Wu Lingqian、Ogi Tomoo、Zhang Huiwen
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

      Volume: 1867 Issue: 6 Pages: 166106-166106

    • DOI

      10.1016/j.bbadis.2021.166106

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Transcription-Coupled DNA Repair: From Mechanism to Human Disorder2021

    • Author(s)
      van den Heuvel Diana、van der Weegen Yana、Boer Daphne E.C.、Ogi Tomoo、Luijsterburg Martijn S.
    • Journal Title

      Trends in Cell Biology

      Volume: 31 Issue: 5 Pages: 359-371

    • DOI

      10.1016/j.tcb.2021.02.007

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Extensive multiple organ involvement in VEXAS syndrome2021

    • Author(s)
      Takahashi Noriyuki、Takeichi Takuya、Nishida Tetsuya、Takahashi Yasuhiro、Sato Juichi、Yamamura Masahiro、Ogi Tomoo、Akiyama Masashi
    • Journal Title

      Arthritis & Rheumatology

      Volume: - Issue: 10 Pages: 1896-1897

    • DOI

      10.1002/art.41775

    • NAID

      120007126470

    • 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 Variants2020

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

      Journal of Investigative Dermatology

      Volume: in press Issue: 6 Pages: 1596-1598

    • DOI

      10.1016/j.jid.2020.09.035

    • NAID

      120007175360

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Expanding the phenotype of biallelic loss‐of‐function variants in the <scp> <i>NSUN2</i> </scp> gene: Description of four individuals with juvenile cataract, chronic nephritis, or brain anomaly as novel complications2020

    • Author(s)
      Kato Kohji、Mizuno Seiji、Morton Jenny、Toyama Miho、Hara Yuichiro、Wasmer Evangeline、Lehmann Alan、Ogi Tomoo
    • Journal Title

      American Journal of Medical Genetics Part A

      Volume: 185 Issue: 1 Pages: 282-285

    • DOI

      10.1002/ajmg.a.61927

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome2020

    • Author(s)
      Oka Y, Hamada M, Nakazawa Y, ..., Tanaka M, Suganami T, Nakada S, Mitsutake N, Hara Y, Kato K, ..., Kaneko H, Matsumoto N, Matsuda F, Matsuo K, Takahashi Y, Mashimo T, Kojima S, Ogi T
    • Journal Title

      Science Advances

      Volume: 6 Issue: 51 Pages: 7197-7197

    • DOI

      10.1126/sciadv.abd7197

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Topoisomerase I-driven repair of UV-induced damage in NER-deficient cells2020

    • Author(s)
      Saha Liton Kumar、Wakasugi Mitsuo、Akter Salma、Prasad Rajendra、Wilson Samuel H.、Shimizu Naoto、Sasanuma Hiroyuki、Huang Shar-yin Naomi、Agama Keli、Pommier Yves、Matsunaga Tsukasa、Hirota Kouji、Iwai Shigenori、Nakazawa Yuka、Ogi Tomoo、Takeda Shunichi
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 117 Issue: 25 Pages: 14412-14420

    • DOI

      10.1073/pnas.1920165117

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair2020

    • Author(s)
      Nakazawa Y, Hara Y, Oka Y, Komine O, van den Heuvel D, Guo C, Daigaku Y, Isono M, He Y, Shimada M, Kato K, Jia N, Hashimoto S, Kotani Y, Miyoshi Y, Tanaka M, Sobue A, Mitsutake N, Suganami T, Masuda A, Ohno K, Nakada S, Mashimo T, Yamanaka K, Luijsterburg MS, Ogi T
    • Journal Title

      Cell

      Volume: 19 Issue: 6 Pages: 1228-1244

    • DOI

      10.1016/j.cell.2020.02.010

    • NAID

      120006871293

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Severe achondroplasia due to two de novo variants in the transmembrane domain of FGFR3 on the same allele: A case report.2020

    • Author(s)
      Nagata T, Matsushita M, Mishima K, Kamiya Y, Kato K, Toyama M, Ogi T, Ishiguro N, Kitoh H.
    • Journal Title

      Molecular Genetics & Genomic Medicine

      Volume: 8 Issue: 3 Pages: 1-1

    • DOI

      10.1002/mgg3.1148

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel NCSTN missense mutation in the signal peptide domain causes hidradenitis suppurativa, which has features characteristic of an autoinflammatory keratinization disease.2020

    • Author(s)
      Takeichi T, Matsumoto T, Nomura T, Takeda M, Niwa H, Kono M, Shimizu H, Ogi T, Akiyama M.
    • Journal Title

      Br J Dermatol.

      Volume: 182 Issue: 2 Pages: 491-493

    • DOI

      10.1111/bjd.18445

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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

      Journal of Dermatological Science

      Volume: 97 Issue: 1 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] Hailey-Hailey disease with oesophageal involvement due to a previously unreported ATP2C1 mutation2019

    • Author(s)
      Kono M, Kodera M, Inasaka Y, Hasegawa I, Muro Y, Nakazawa Y, Ogi T, Akiyama M.
    • Journal Title

      European Journal of Dermatology

      Volume: 印刷中

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype.2019

    • Author(s)
      Theil AF, Botta E, Raams A, Smith DEC, Mendes MI, Caligiuri G, Giachetti S, Bione S, Carriero R, Liberi G, Zardoni L, Swagemakers SMA, Salomons GS, Sarasin A, Lehmann A, van der Spek PJ, Ogi T, Hoeijmakers JHJ, Vermeulen W, Orioli D.
    • Journal Title

      American Journal of Human Genetics

      Volume: 105 Issue: 2 Pages: 434-440

    • DOI

      10.1016/j.ajhg.2019.06.017

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The JAK/STAT3 and NF-kappa B signaling pathways regulate cancer stem cell properties in anaplastic thyroid cancer cells2019

    • Author(s)
      K. Shiraiwa, M. Mitsutake, Y. Nakazawa, T. Ogi, K. Suzuki, V. Saenko, K. Umezawa, S. Yamashita, K. Tsukamoto
    • Journal Title

      Thyroid

      Volume: in press Issue: 5 Pages: 674-682

    • DOI

      10.1089/thy.2018.0212

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A Japanese Case of Galli-Galli Disease due to a Previously Unreported POGLUT1 Mutation2019

    • Author(s)
      Kono M、Sawada M、Nakazawa Y、Ogi T、Muro Y、Akiyama M
    • Journal Title

      Acta Dermato Venereologica

      Volume: 99 Issue: 4 Pages: 458-459

    • DOI

      10.2340/00015555-3119

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional Comparison of XPF Missense Mutations Associated to Multiple DNA Repair Disorders2019

    • Author(s)
      Marin M, Ramirez MJ, Carmona MA, Jia N, Ogi T, Bogliolo M, Surralles J.
    • Journal Title

      Genes

      Volume: 10 Issue: 1 Pages: 60-60

    • DOI

      10.3390/genes10010060

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome.2018

    • Author(s)
      Calmels N, Botta E, Jia N, Fawcett H, Nardo T, Nakazawa Y, Lanzafame M, Moriwaki S, Sugita K, Kubota M, Obringer C, Spitz MA, Stefanini M, Laugel V, Orioli D, Ogi T, Lehmann A.
    • Journal Title

      Journal of Medical Genetics

      Volume: 55 Issue: 5 Pages: 329-343

    • DOI

      10.1136/jmedgenet-2017-104877

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations2018

    • Author(s)
      Doi H、Koyano S、Miyatake S、Nakajima S、Nakazawa Y、Kunii M、Tomita-Katsumoto A、Oda K、Yamaguchi Y、Fukai R、Ikeda S、Kato R、Ogata K、Kubota S、Hayashi N、Takahashi K、Tada M、Tanaka K、Nakashima M、Tsurusaki Y et al.
    • Journal Title

      Journal of Human Genetics

      Volume: 63 Issue: 4 Pages: 417-423

    • DOI

      10.1038/s10038-017-0408-5

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] プロテオーム解析を用いたDNA損傷応答機構の破綻により発症する遺伝性疾患の分子病態解明2021

    • Author(s)
      岡泰由、荻朋男
    • Organizer
      日本放射線影響学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] RNA polymerase IIのユビキチン化修飾による転写共役修復開始反応の分子機構とその破綻により発症する哺乳類の神経変性のメカニズム.2019

    • Author(s)
      荻朋男
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 転写共役ヌクレオチド除去修復機構に重要なRNAポリメラーゼユビキチン化部位の同定2019

    • Author(s)
      中沢由華, 原雄一郎, 岡泰由, 小峯起, Diana van den Heuvel, 郭朝万, 大学保一, 磯野真由, 何予希, 嶋田繭子, 加藤香奈, 賈楠, 橋下悟, 小谷祐子, 三好由夏, 田中都, 祖父江顕, 光武範吏, 菅波孝祥, 増田章男, 大野欽司, 中田慎一郎, 真下知士, 山中宏二, Martijn S. Luijsterburg, 荻朋男
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ChIP-seqを利用したDNA損傷およびヌクレオチド除去修復のモニタリング.2019

    • Author(s)
      原雄一郎, 中沢由華, 岡泰由, 小峯起, Diana van den Heuvel, 郭朝万, 大学保一, 磯野真由, 何予希, 嶋田繭子, 加藤香奈, 賈楠, 橋下悟, 小谷祐子, 三好由夏, 田中都, 祖父江顕, 光武範吏, 菅波孝祥, 増田章男, 大野欽司, 中田慎一郎, 真下知士, 山中宏二, Martijn S. Luijsterburg, 荻朋男.
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] VPS35Lの両アレルにおける機能喪失型バリアントは 3C/Ritscher-Schinzel 症候群に類似の先天異 常症候群の原因となる2019

    • Author(s)
      加藤耕治, 岡泰由, 村松秀城, Vasilev F, 大友孝信, 大石久史, 河野好彦, 中沢由華, 荻朋男, 高橋義行, 齋藤伸治.
    • Organizer
      日本人類遺伝学会第64回大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 希少未診断疾患におけるゲノム解析およびデータ評価パイプラインの構築2019

    • Author(s)
      中沢由華, 原雄一郎, 遠山美穂, 岡泰由, 荻朋男.
    • Organizer
      第4回名大医薬系3部局交流シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex2019

    • Author(s)
      Kato K, Oka Y, Muramatsu H, Vasilev F, Otomo T, Oishi H, Kawano Y, Nakazawa Y, Ogi T, Takahashi Y, Saitoh S.
    • Organizer
      ASHG 2019 Annual Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] マルチオミクス解析により同定した重症アイカルディ・ゴーティエ症候群の分子病態解析.2019

    • Author(s)
      岡 泰由, 荻 朋男.
    • Organizer
      第41回日本小児遺伝学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Alterations in RNA polymerase IIo ubiquitination cause Cockayne syndrome-like premature aging phenotype in mice due to TC-NER defect.2019

    • Author(s)
      Ogi T.
    • Organizer
      International Symposium on XP and other Nucleotide Excision Repair Disorders
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Alterations in RNA polymerase IIo ubiquitination cause Cockayne syndrome-like premature aging phenotype in mice due to TC-NER defect.2019

    • Author(s)
      Nakazawa Y, Ogi T.
    • Organizer
      International Symposium on XP and other Nucleotide Excision Repair Disorders
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ゲノム不安定性疾患群を中心とした希少難治性疾患の次世代マルチオミクス解析と難病プラットフォーム連携による疾患原因変異の検索.2019

    • Author(s)
      荻 朋男.
    • Organizer
      難病プラットフォーム公開シンポジウム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] DNA損傷依存的なRNAポリメラーゼのユビキチン化修飾の異常はDNA修復経路の欠損マウスで老化表現型を示す.2019

    • Author(s)
      荻 朋男.
    • Organizer
      国立遺伝学研究所・研究集会「ゲノムの維持継承を支える分子基盤の包括的理解とその発展」
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Identification of pathogenic mutations in patients with rare diseases using multiomics approaches.2018

    • Author(s)
      Oka Y, Ogi T.
    • Organizer
      Japanese Proteomics Society 2018 Conference (JPrOS 2018), 9th Asia-Oceania Human Proteome Organization (AOHUPO), and 66th Annual Conference on Mass Spectrometry
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ゲノム不安定性を示す遺伝性疾患の分子病態.2018

    • Author(s)
      中沢由華, 荻 朋男.
    • Organizer
      第3回名大医薬系3部局交流シンポジウム~岐阜薬科大学・岐阜大学G-CHAIN・ラクオリア創薬合同シンポジウム~
    • Related Report
      2018 Annual Research Report
  • [Presentation] RNAポリメラーゼのユビキチン化修飾による転写共役ヌクレオチド除去修復の反応制御とコケイン症候群の病態.2018

    • Author(s)
      荻 朋男.
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] コケイン症候群の疾患責任遺伝子変異を特定する解析方法について.2018

    • Author(s)
      荻 朋男, 中沢由華.
    • Organizer
      コケイン症候群勉強会
    • Related Report
      2018 Annual Research Report
  • [Remarks] 名古屋大学環境医学研究所HP

    • URL

      http://www.riem.nagoya-u.ac.jp/index.html

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report 2018 Annual Research Report
  • [Remarks] 名古屋大学環境医学研究所 発生遺伝分野HP

    • URL

      http://www.riem.nagoya-u.ac.jp/4/genetics/index.html

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report 2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 造血不全、発育遅滞、高発がん性、精神機能障害のモデル動物2020

    • Inventor(s)
      荻朋男、岡泰由
    • Industrial Property Rights Holder
      荻朋男、岡泰由
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-166756
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 老化マウスモデル2019

    • Inventor(s)
      荻朋男
    • Industrial Property Rights Holder
      名古屋大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-203237
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report

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Published: 2018-04-23   Modified: 2023-01-30  

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