Updated on 2024/10/16

写真a

 
WATANABE Takahiro
 
Organization
Graduate School of Medicine Program in Integrated Medicine Microbiology and Immunology Assistant Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Assistant Professor
Contact information
メールアドレス

Degree 1

  1. 博士(医学) ( 2016.3   名古屋大学 ) 

Research Interests 3

  1. 口腔外科学

  2. ウイルス学

  3. 腫瘍ウイルス学

Research Areas 2

  1. Life Science / Surgical dentistry

  2. Life Science / Virology

Research History 6

  1. Nagoya University   Assistant

    2017.10

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    Country:Japan

  2. Aichi Gakuin University

    2017.1

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    Country:Japan

  3. Nagoya University

    2016.4 - 2017.9

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    Country:Japan

  4. Fujita Health University

    2013.4

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    Country:Japan

  5. Fujita Health University   Assistant

    2011.4 - 2013.3

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    Country:Japan

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Education 1

  1. Nagoya University   Graduate School, Division of Medical Sciences

    - 2016.3

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    Country: Japan

Professional Memberships 5

  1. 日本有病者歯科医療学会   専門医

  2. 日本口腔外科学会   認定医

  3. 日本ウイルス学会

  4. 日本癌学会

  5. 日本臨床ウイルス学会

Committee Memberships 2

  1.   実験動物部門利用委員  

    2020.4 - 2023.6   

  2.   個人情報取扱委員  

    2017.10 - 2023.6   

Awards 3

  1. 2022年度 海外留学助成

    2022   公益財団法人 国際医学研究振興財団  

  2. 優秀ポスター発表賞 第66回日本口腔外科学会総会学術大会

    2021.11   EBウイルス関連腫瘍のがん微小環境における炎症性細胞浸潤メカニズムの解析

  3. 優秀ポスター発表賞

    2017.10   第62回日本口腔外科学会総会学術大会  

    渡辺 崇広

 

Papers 37

  1. Epstein-Barr virus lytic gene BNRF1 promotes B-cell lymphomagenesis via IFI27 upregulation. International journal

    Ken Sagou, Yoshitaka Sato, Yusuke Okuno, Takahiro Watanabe, Tomoki Inagaki, Yashiro Motooka, Shinya Toyokuni, Takayuki Murata, Hitoshi Kiyoi, Hiroshi Kimura

    PLoS pathogens   Vol. 20 ( 2 ) page: e1011954   2024.2

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    Language:English   Publishing type:Research paper (scientific journal)  

    Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus that is causally associated with several malignancies. In addition to latent factors, lytic replication contributes to cancer development. In this study, we examined whether the lytic gene BNRF1, which is conserved among gamma-herpesviruses, has an important role in lymphomagenesis. We found that lymphoblastoid cell lines (LCLs) established by BNRF1-knockout EBV exhibited remarkably lower pathogenicity in a mice xenograft model than LCLs produced by wild-type EBV (LCLs-WT). RNA-seq analyses revealed that BNRF1 elicited the expression of interferon-inducible protein 27 (IFI27), which promotes cell proliferation. IFI27 knockdown in LCLs-WT resulted in excessive production of reactive oxygen species, leading to cell death and significantly decreased their pathogenicity in vivo. We also confirmed that IFI27 was upregulated during primary infection in B-cells. Our findings revealed that BNRF1 promoted robust proliferation of the B-cells that were transformed by EBV latent infection via IFI27 upregulation both in vitro and in vivo.

    DOI: 10.1371/journal.ppat.1011954

    Web of Science

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  2. Growth Transformation of B Cells by Epstein-Barr Virus Requires <i>IMPDH2</i> Induction and Nucleolar Hypertrophy

    Atsuko Sugimoto, Takahiro Watanabe, Kazuhiro Matsuoka, Yusuke Okuno, Yusuke Yanagi, Yohei Narita, Seiyo Mabuchi, Hiroyuki Nobusue, Eiji Sugihara, Masaya Hirayama, Tomihiko Ide, Takanori Onouchi, Yoshitaka Sato, Teru Kanda, Hideyuki Saya, Yasumasa Iwatani, Hiroshi Kimura, Takayuki Murata

    Microbiology Spectrum   Vol. 11 ( 4 ) page: e0044023   2023.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Society for Microbiology  

    EBV infections cause nucleolar enlargement via the induction of IMPDH2, which are essential for B cell growth transformation by EBV. Although the significance of IMPDH2 induction and nuclear hypertrophy in the tumorigenesis of glioblastoma has been reported, EBV infection brings about the change quickly by using its transcriptional cofactor, EBNA2, and MYC. Moreover, we present here, for the novel, basic evidence that an IMPDH2 inhibitor, namely, MPA or MMF, can be used for EBV-positive posttransplant lymphoproliferative disorder (PTLD).

    DOI: 10.1128/spectrum.00440-23

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  3. Epstein-Barr Virus BBLF1 Mediates Secretory Vesicle Transport to Facilitate Mature Virion Release. International journal

    Md Kamal Uddin, Takahiro Watanabe, Masataka Arata, Yoshitaka Sato, Hiroshi Kimura, Takayuki Murata

    Journal of virology   Vol. 97 ( 6 ) page: e0043723   2023.6

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    Language:English   Publishing type:Research paper (scientific journal)  

    Enveloped viruses undergo a complex multistep process of assembly, maturation, and release into the extracellular space utilizing host secretory machinery. Several studies of the herpesvirus subfamily have shown that secretory vesicles derived from the trans-Golgi network (TGN) or endosomes transport virions into the extracellular space. However, the regulatory mechanism underlying the release of Epstein-Barr virus, a human oncovirus, remains unclear. We demonstrate that disruption of BBLF1, a tegument component, suppressed viral release and resulted in the accumulation of viral particles on the inner side of the vesicular membrane. Organelle separation revealed the accumulation of infectious viruses in fractions containing vesicles derived from the TGN and late endosomes. Deficiency of an acidic amino acid cluster in BBLF1 reduced viral secretion. Moreover, truncational deletion of the C-terminal region of BBLF1 increased infectious virus production. These findings suggest that BBLF1 regulates the viral release pathway and reveal a new aspect of tegument protein function. IMPORTANCE Several viruses have been linked to the development of cancer in humans. Epstein-Barr virus (EBV), the first identified human oncovirus, causes a wide range of cancers. Accumulating literature has demonstrated the role of viral reactivation in tumorigenesis. Elucidating the functions of viral lytic genes induced by reactivation, and the mechanisms of lytic infection, is essential to understanding pathogenesis. Progeny viral particles synthesized during lytic infection are released outside the cell after the assembly, maturation, and release steps, leading to further infection. Through functional analysis using BBLF1-knockout viruses, we demonstrated that BBLF1 promotes viral release. The acidic amino acid cluster in BBLF1 was also important for viral release. Conversely, mutants lacking the C terminus exhibited more efficient virus production, suggesting that BBLF1 is involved in the fine-tuning of progeny release during the EBV life cycle.

    DOI: 10.1128/jvi.00437-23

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  4. Comprehensive Analyses of Intraviral Epstein-Barr Virus Protein-Protein Interactions Hint Central Role of BLRF2 in the Tegument Network. International journal

    Yuya Hara, Takahiro Watanabe, Masahiro Yoshida, H M Abdullah Al Masud, Hiromichi Kato, Tomohiro Kondo, Reiji Suzuki, Shutaro Kurose, Md Kamal Uddin, Masataka Arata, Shouhei Miyagi, Yusuke Yanagi, Yoshitaka Sato, Hiroshi Kimura, Takayuki Murata

    Journal of virology   Vol. 96 ( 14 ) page: e0051822   2022.7

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Protein-protein interactions (PPIs) are crucial for various biological processes. Epstein-Barr virus (EBV) proteins typically form complexes, regulating the replication and persistence of the viral genome in human cells. However, the role of EBV protein complexes under physiological conditions remains unclear. In this study, we performed comprehensive analyses of EBV PPIs in living cells using the NanoBiT system. We identified 195 PPIs, many of which have not previously been reported. Computational analyses of these PPIs revealed that BLRF2, which is only found in gammaherpesviruses, is a central protein in the structural network of EBV tegument proteins. To characterize the role of BLRF2, we generated two BLRF2 knockout EBV clones using CRISPR/Cas9. BLRF2 knockout significantly decreased the production of infectious virus particles, which was partially restored by exogenous BLRF2 expression. In addition, self-association of BLRF2 protein was found, and mutation of the residues crucial for the self-association affected stability of the protein. Our data imply that BLRF2 is a tegument network hub that plays important roles in progeny virion maturation. IMPORTANCE EBV remains a significant public health challenge, causing infectious mononucleosis and several cancer types. Therefore, the better understanding of the molecular mechanisms underlying EBV replication is of high clinical importance. As protein-protein interactions (PPIs) are major regulators of virus-associated pathogenesis, comprehensive analyses of PPIs are essential. Previous studies on PPIs in EBV or other herpesviruses have predominantly employed the yeast two-hybrid (Y2H) system, immunoprecipitation, and pulldown assays. Herein, using a novel luminescence-based method, we identified 195 PPIs, most of which have not previously been reported. Computational and functional analyses using knockout viruses revealed that BLRF2 plays a central role in the EBV life cycle, which makes it a valuable target for drug development.

    DOI: 10.1128/jvi.00518-22

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  5. Epstein-Barr virus tegument protein BGLF2 in exosomes released from virus-producing cells facilitates de novo infection. International journal

    Yoshitaka Sato, Masahiro Yaguchi, Yusuke Okuno, Hanako Ishimaru, Ken Sagou, Somi Ozaki, Takeshi Suzuki, Tomoki Inagaki, Miki Umeda, Takahiro Watanabe, Masahiro Fujimuro, Takayuki Murata, Hiroshi Kimura

    Cell communication and signaling : CCS   Vol. 20 ( 1 ) page: 95 - 95   2022.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    BACKGROUND: Viruses must adapt to the environment of their host cells to establish infection and persist. Diverse mammalian cells, including virus-infected cells, release extracellular vesicles such as exosomes containing proteins and miRNAs, and use these vesicles to mediate intercellular communication. However, the roles of exosomes in viral infection remain unclear. RESULTS: We screened viral proteins to identify those responsible for the exosome-mediated enhancement of Epstein-Barr virus (EBV) infection. We identified BGLF2 protein encapsulated in exosomes, which were released by EBV-infected cells. BGLF2 protein is a tegument protein that exists in the space between the envelope and nucleocapsid, and it is released into the cytoplasm shortly after infection. BGLF2 protein-containing exosomes enhanced viral gene expression and repressed innate immunity, thereby supporting the EBV infection. CONCLUSIONS: The EBV tegument protein BGLF2 is encapsulated in exosomes and released by infected cells to facilitate the establishment of EBV infection. These findings suggest that tegument proteins support viral infection not only between the envelope and nucleocapsid, as well as in extraviral particles such as exosomes. Video abstract.

    DOI: 10.1186/s12964-022-00902-7

    Web of Science

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Books 1

  1. 最先端ナノライフシステム研究_電子版

    佐藤好隆、渡辺崇広、三宅康之、木村宏(重症ウイルス感染症/ウイルス関連腫瘍を制御するための宿主因子探索と創薬応用)

    2022.3 

Presentations 6

  1. 医療安全に関する知識Ⅰ 院内感染対策について Invited

    2022年度 愛知県⻭科衛生士会研修会  2023.1.28  愛知県歯科衛生士会

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    Event date: 2023.1 - 2023.2

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:オンデマンド配信  

  2. Endosomal Deubiquitinase Usp7 Promotes Influenza Virus Uncoating International conference

    Rozanova A, Watanabe T, Narita N, Kimura H, Miyake Y

    NSV 2022  2022.6 

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    Event date: 2022.6

    Language:English   Presentation type:Oral presentation (general)  

  3. Epstein-Barr Virus BBLF1 is Involved in Efficient Virus Egress International conference

    Watanabe T, Uddin Md, Kimura H, Murata T.

    ASM Microbe 2022  2022.6.10 

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    Event date: 2022.6

    Language:English   Presentation type:Poster presentation  

  4. 新型コロナウイルスについて −ウイルス学と歯科臨床の両方の視点で Invited

    愛知県歯科医学大会2021, (公社) 愛知県歯科衛生士会, 招待講演  2021.2.21 

  5. 診療室における感染予防の 基本と実際 Invited

    公益社団法人 愛知県歯科衛生士会主催, 診療室における感染予防の 基本と実際, R2年度“卒後1~3年のための研修会”  2021.1.10 

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Research Project for Joint Research, Competitive Funding, etc. 8

  1. Research on Symbiotic Microbiota-derived Extracellular Vesicles in Immunometabolism

    2023.7

  2. Epstein-Barrウイルスが有する核酸認識受容体を介した自然免疫応答からの回避機構の解析

    2021

    堀科学芸術振興財団 

  3. EBウイルスにより細胞老化制御機構の解明

    2020

    共済団 医学研究奨励助成金 

  4. 遺伝子変異型EBVの造腫瘍性において果たす意義を解明する

    2019

    北村記念血液疾患研究基金 

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    Grant type:Competitive

  5. 網羅的プロテオーム解析で解くEBウイルス発癌の分子機構

    2019

    第44回がんその他の悪性新生物研究助成金 

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    Grant type:Competitive

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KAKENHI (Grants-in-Aid for Scientific Research) 5

  1. エンベロープウイルスの膜融合タンパク質に着目した自然免疫回避機構の解明

    Grant number:22KK0274  2022

    日本学術振興会  科学研究費助成事業  国際共同研究加速基金(国際共同研究強化(A))

    渡辺 崇広

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    Authorship:Principal investigator 

    Grant amount:\15470000 ( Direct Cost: \11900000 、 Indirect Cost:\3570000 )

  2. EBウイルスの病原体認識回避機構の解明

    Grant number:21K15449  2021.4 - 2024.3

    若手研究

    渡辺 崇広

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    Authorship:Principal investigator 

    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    Epstein-Barr virus (EBV) は、生体防御を担う免疫応答を巧みにコントロールし、免疫平衡の状態で生涯感染を維持することができる。この免疫平衡状態が何らかの理由で破綻すると、EBV関連がんを発症する。本研究では、EBV遺伝子発現ライブラリを用いて特に自然免疫制御機構に着目したスクリーニングを行い、この過程に関わるウイルス因子を同定する。さらに同定したウイルス因子を標的とした遺伝子組換えウイルスを構築し、EBVの造腫瘍性を再現したヒト化マウスモデルを用いたin vivoでの検証を実施し、生体におけるEBVと自然免疫との共進化および発がん機構の解明を推進する。

  3. 欠失EBVによるリンパ腫発生機構の解明

    Grant number:20H03493  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    木村 宏

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    Authorship:Coinvestigator(s) 

    我々は慢性活動性Epstein-Barr virus (EBV) 感染症に対して、網羅的遺伝子解析を行い、高率にEBV遺伝子の一部が欠失していることを発見した。本研究では、欠失ウイルスがEBV関連腫瘍で普遍的にみられる事象なのか、一部の疾患に限定しているのかを明らかにする。具体的には、様々なEBV関連腫瘍の腫瘍組織を集積し、Whole EBVシーケンシングを行う。この過程で、疾患特異的に欠失しているEBV遺伝子を同定する。次いで、それらのEBV遺伝子を欠失した変異ウイルスを再現・作成し、培養細胞を用いたin vitroおよびヒト化マウスを用いたin vivoモデルにより、当該遺伝子の役割を解明する。

  4. ヒト化マウスモデルを用いたEBV関連リンパ増殖症の病態解析と新たな標的治療の評価

    2018.4

    科学研究費補助金 

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    Authorship:Principal investigator 

  5. 遺伝子改変EBウイルスとヒト化マウスを用いたリンパ増殖性疾患の発症病理の解析

    2016.10 - 2018.3

    科学研究費補助金 

Industrial property rights 1

  1. Cyclin dependent kinase(CDK)阻害剤によるEpstein-Barrウイルスのウイルス産生抑制

    佐藤好隆、木村宏、渡辺崇広

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    Application no:特願2017-250093  Date applied:2017.12

    Country of applicant:Domestic  

 

Teaching Experience (On-campus) 6

  1. ウイルス学総論6

    2022

  2. ウイルス学実習

    2022

  3. ウイルス学総論4

    2022

  4. ウイルス学総論4

    2020

  5. ウイルス学総論6

    2020

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Teaching Experience (Off-campus) 1

  1. DNAウイルスとヘルペスウイルス

    2021 Nagoya City University)

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    Level:Undergraduate (specialized) 

 

Academic Activities 1

  1. 名大MIRAI GSC

    2018

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    Type:Scientific advice/Review