柴田　淳史 （シバタ　アツシ）

Shibata, Atsushi

写真a

所属（所属キャンパス）

薬学部 薬学科 （芝共立）

職名

教授

HP
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経歴 【 表示 ／ 非表示 】

  • 2004年
    -
    2006年

    東京医科歯科大学, 日本学術振興会 特別研究員DC1

  • 2006年
    -
    2007年

    東京医科歯科大学, 日本学術振興会 特別研究員PD

  • 2006年
    -
    2007年

    東京医科歯科大学, Medical and Dental Sciences Postdoctoral Degree (Ph.D, medicine)

  • 2006年
    -
    2012年

    University of Sussex, 博士研究員

  • 2012年
    -
    2013年

    University of Sussex, 日本学術振興会 海外特別研究員

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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 分子生物学

  • ライフサイエンス / 遺伝学

  • ライフサイエンス / 病態医化学

  • ライフサイエンス / 放射線科学

  • 環境・農学 / 放射線影響

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研究キーワード 【 表示 ／ 非表示 】

  • DNA修復

  • DNA損傷

  • がん免疫治療（PD-L1, HLA, Neoantigen）

  • がん治療

  • クロマチン

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著書 【 表示 ／ 非表示 】

  • Carbon ion radiation and clustered DNA double-strand breaks

    Atsushi Shibata, Academic Press, 2022年,  ページ数： 117-130

    担当範囲: Chapter eight 原著者： Fuyuhiko Tamanoi, Kenichi Yoshikawa

    　概要を見る

    A carbon ion categorized as a heavy ion particle has been used for cancer radiotherapy. High linear energy transfer (LET) carbon ion irradiation deposits energy at a high density along a particle track, generating multiple types of DNA damage. Complex DNA lesions, comprising DNA double-strand breaks (DSBs), single-strand breaks, and base damage within 1–2 helical turns (< 3–4 nm), are thought to be difficult to repair and critically influence cell viability. In addition to the effect of lesion complexity, the most recent studies have demonstrated another characteristic of high LET particle radiation-induced DNA damage, clustered DSBs. Clustered DSBs are defined as the formation of multiple DSBs in close proximity where the scale of clustering is approximately 1–2 μm3, i.e., the scale of the event is estimated to be > ∼ 1 Mbp. This chapter reviews the hallmarks of clustered DSBs and how such DNA damage influences genome instability and cell viability in the context of high LET carbon ion radiotherapy.

  • Other Determinants of Sensitivity

    Naoyuki Okita, Atsushi Shibata他, Humana Press, 2015年06月,  ページ数： 363-379

    原著者： Nicola J. Curtin, Ricky A. Sharma , 査読有り

    　概要を見る

    Cancer treatments such as radiotherapy and chemotherapy induce DNA damage, which can be a factor determining therapeutic efficacy. A DNA double strand break (DSB) is considered to be the most critical type of DNA lesion, since DSBs cause cell death when they are unrepaired and generate mutations if they are misrepaired. Ionising radiation (IR) produces a broad spectrum of DNA damage, including DSBs, single strand breaks (SSBs) and base damages. Specific poly(ADP-ribose)polymerase (PARP) inhibitors, currently being tested in clinical trials, compromise SSB repair after IR, resulting in the accumulation of replication-associated DSBs. Since replication-associated DSBs are effectively repaired by homologous recombination, PARP inhibition sensitizes cells that are defective in homologous recombination. In addition, PARP inhibition effectively blocks backup DSB repair in cells defective in non-homologous end joining (NHEJ) following IR. Importantly, the sensitization in NHEJ-defective cells occurs independently of DNA replication. In this chapter, we discuss the multiple effects of PARP inhibition in DSB repair-defective cells in the context of the potential availability of PARP inhibitor in clinical use. We further discuss how a PARP inhibitor influences the type of cell death, which may affect prognosis following cancer treatment. In cancer therapy using PARP inhibitors, a comprehensive understanding of PARP signaling from DNA damage to cell death may be required to augment DNA damage-induced cell death and to direct restrained cell death in order to reduce inflammation responses in surrounding tissues.

  • Agent-dependent effects of Parp-1 deficiency on DNA damage responses and genomic stability in mouse ES cells

    Hideki Ogino, Atsushi Shibata, Akemi Gunji, Hiroshi Suzuki, Hitoshi Nakagawa, Takashi Sugimura, Mitsuko Masutani, nova science publishers, 2006年04月,  ページ数： 133-147

    担当範囲: Chapter6 原著者： Erik V. Greer

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  • ATR signaling controls the bystander responses of human chondrosarcoma cells by promoting RAD51-dependent DNA repair

    Nho Cong Luong, Hidemasa Kawamura, Hiroko Ikeda, Reiko T. Roppongi, Atsushi Shibata, Jiaxuan Hu, Jinmeng G. Jiang, David S. Yu, Kathryn D. Held

    International Journal of Radiation Biology （Taylor & Francis group）     1 - 12 2024年

    研究論文（学術雑誌）, 共著, 査読有り

    　概要を見る

    Purpose
    Radiation-induced bystander effect (RIBE) frequently is seen as DNA damage in unirradiated bystander cells, but the repair processes initiated in response to that DNA damage are not well understood. RIBE-mediated formation of micronuclei (MN), a biomarker of persistent DNA damage, was previously observed in bystander normal fibroblast (AG01522) cells, but not in bystander human chondrosarcoma (HTB94) cells. The molecular mechanisms causing this disparity are not clear. Herein, we investigate the role of DNA repair in the bystander responses of the two cell lines.

    Methods
    Cells were irradiated with X-rays and immediately co-cultured with un-irradiated cells using a trans-well insert system in which they share the same medium. The activation of DNA damage response (DDR) proteins was detected by immunofluorescence staining or Western blotting. MN formation was examined by the cytokinesis-block MN assay, which is a robust method to detect persistent DNA damage.

    Results
    Immunofluorescent foci of γH2AX and 53BP1, biomarkers of DNA damage and repair, revealed a greater capacity for DNA repair in HTB94 cells than in AG01522 cells in both irradiated and bystander populations. Autophosphorylation of ATR at the threonine 1989 site was expressed at a greater level in HTB94 cells compared to AG01522 cells at the baseline and in response to hydroxyurea treatment or exposure to 1 Gy of X-rays. An inhibitor of ATR, but not of ATM, promoted MN formation in bystander HTB94 cells. In contrast, no effect of either inhibitor was observed in bystander AG01522 cells, indicating that ATR signaling might be a pivotal pathway to preventing the MN formation in bystander HTB94 cells. Supporting this idea, we found an ATR-dependent increase in the fractions of bystander HTB94 cells with pRPA2 S33 and RAD51 foci. A blocker of RAD51 facilitated MN formation in bystander HTB94 cells.

    Conclusion
    Our results indicate that HTB94 cells were likely more efficient in DNA repair than AG01522 cells, specifically via ATR signaling, which inhibited the bystander signal-induced MN formation. This study highlights the significance of DNA repair efficiency in bystander cell responses.

  • Characterization of the signal transduction cascade for inflammatory gene expression in fibroblasts with ATM-ATR deficiencies after Ionizing radiation

    Shunji Haruna, Ken Okuda, Akiko Shibata, Mayu Isono, Kohei Tateno, Hiro Sato, Takahiro Oike, Yuki Uchihara, Yu Kato, Atsushi Shibata

    Radiotherapy and Oncology （Elsevier）  194   110198 2024年

    研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

    　概要を見る

    Background and purpose
    Ionizing radiation (IR) induces DNA double-strand breaks (DSBs), leading to micronuclei formation, which has emerged as a key mediator of inflammatory responses after IR. This study aimed to investigate the signaling cascade in inflammatory gene expression using fibroblasts harboring DNA damage response deficiency after exposure to IR.
    Materials and methods
    Micronuclei formation was examined in human dermal fibroblasts derived from patients with deficiencies in ATM, ATR, MRE11, XLF, Artemis, or BRCA2 after IR. RNA-sequencing analysis was performed to assess gene expression, pathway mapping, and the balance of transcriptional activity using the transcription factor–based downstream gene expression mapping (TDEM) method developed in this study.
    Results
    Deficiencies in ATM, ATR, or MRE11 led to increased micronuclei formation after IR compared to normal cells. RNA-seq analysis revealed significant upregulation of inflammatory expression in cells deficient in ATM, ATR, or MRE11 following IR. Pathway mapping analysis identified the upregulation of RIG-I, MDA-5, IRF7, IL6, and interferon stimulated gene expression after IR. These changes were pronounced in cells deficient in ATM, ATR, or MRE11. TDEM analysis suggested the differential activation of STAT1/3–pathway between ATM and ATR deficiency.
    Conclusion
    Enhanced micronuclei formation upon ATM, ATR, or MRE11 deficiency activated the cGAS/STING, RIG-I-MDA-5-IRF7-IL6 pathway, resulting in its downstream interferon stimulated gene expression following exposure to IR. Our study provides comprehensive information regarding the status of inflammation-related gene expression under DSB repair deficiency after IR. The generated dataset may be useful in developing functional biomarkers to accurately identify patients sensitive to radiotherapy.

  • Inhibition of intracellular ATP synthesis impairs the recruitment of homologous recombination factors after ionizing radiation

    Ryota Hayashi, Hikaru Okumura, Mayu Isono, Motohiro Yamauchi, Daiki Unami, Rahmartani Tania Lusi, Masamichi Yamamoto, Yu Kato, Yuki Uchihara, Atsushi Shibata

    Journal of Radiation Research （Oxford University Press）  2024年

    研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

    　概要を見る

    Ionizing radiation (IR)-induced double-strand breaks (DSBs) are primarily repaired by non-homologous end joining or homologous recombination (HR) in human cells. DSB repair requires adenosine-5′-triphosphate (ATP) for protein kinase activities in the multiple steps of DSB repair, such as DNA ligation, chromatin remodeling, and DNA damage signaling via protein kinase and ATPase activities. To investigate whether low ATP culture conditions affect the recruitment of repair proteins at DSB sites, IR-induced foci were examined in the presence of ATP synthesis inhibitors. We found that p53 binding protein 1 foci formation was modestly reduced under low ATP conditions after IR, although phosphorylated histone H2AX and mediator of DNA damage checkpoint 1 foci formation were not impaired. Next, we examined the foci formation of breast cancer susceptibility gene I (BRCA1), replication protein A (RPA) and radiation 51 (RAD51), which are HR factors, in G2 phase cells following IR. Interestingly, BRCA1 and RPA foci in the G2 phase were significantly reduced under low ATP conditions compared to that under normal culture conditions. Notably, RAD51 foci were drastically impaired under low ATP conditions. These results suggest that HR does not effectively progress under low ATP conditions; in particular, ATP shortages impair downstream steps in HR, such as RAD51 loading. Taken together, these results suggest that the maintenance of cellular ATP levels is critical for DNA damage response and HR progression after IR.

  • Involvement of the splicing factor SART1 in the BRCA1-dependent homologous recombination repair of DNA double-strand breaks

    Kie Ozaki, Reona Kato, Takaaki Yasuhara, Yuki Uchihara, Miyako Hirakawa, Yu Abe, Hiroki Shibata, Reika Kawabata-Iwakawa, Aizhan Shakayeva, Palina Kot, Kiyoshi Miyagawa, Keiji Suzuki, Naoki Matsuda, Atsushi Shibata & Motohiro Yamauchi

    Scientific Reports 14(1):18455 2024年

    査読有り

  • Comprehensive single cell analysis demonstrates radiotherapy-induced infiltration of macrophages expressing immunosuppressive genes into tumour in oesophageal squamous cell carcinoma

    Hidekazu Oyoshi, Junyan Du, Shunsuke A Sakai, Riu Yamashita, Masayuki Okumura, Atsushi Motegi, Hidehiro Hojo, Masaki Nakamura, Hidenari Hirata, Hironori Sunakawa, Daisuke Kotani, Tomonori Yano, Takashi Kojima, Yuka Nakamura, Motohiro Kojima, Ayako Suzuki, Junko Zenkoh, Katsuya Tsuchihara, Tetsuo Akimoto, Atsushi Shibata, Yutaka Suzuki, Shun-Ichiro Kageyama

    Science Advances （American Association for the Advancement of Science）  9 （ 50 ）  2023年12月

    研究論文（学術雑誌）, 共著, 責任著者, 査読有り

    　概要を見る

    Radiotherapy (RT) combined with immunotherapy is promising; however, the immune response signature in the clinical setting after RT remains unclear. Here, by integrative spatial and single-cell analyses using multiplex immunostaining (CODEX), spatial transcriptome (VISIUM), and single-cell RNA sequencing, we substantiated the infiltration of immune cells into tumors with dynamic changes in immunostimulatory and immunosuppressive gene expression after RT. In addition, our comprehensive analysis uncovered time- and cell type–dependent alterations in the gene expression profile after RT. Furthermore, myeloid cells showed prominent up-regulation of immune response–associated genes after RT. Notably, a subset of infiltrating tumor-associated myeloid cells showing PD-L1 positivity exhibited significant up-regulation of immunostimulatory (HMGB1 and ISG15), immunosuppressive (SIRPA and IDO1), and protumor genes (CXCL8, CCL3, IL-6, and IL-1AB), which can be targets of immunotherapy in combination with PD-L1. These datasets will provide information on the RT-induced gene signature to seek an appropriate target for personalized immunotherapy combined with RT and guide the timing of combination therapy.

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総説・解説等 【 表示 ／ 非表示 】

  • Regulation of DNA damage-induced HLA Class I presentation

    Yuki Uchihara, Atsushi Shibata

    DNA Repair （Elsevier B.V.）  132   103590 2023年12月

    記事・総説・解説・論説等（学術雑誌）, 共著, 最終著者, 責任著者

    　概要を見る

    Immune checkpoint inhibitors (ICI) are cancer therapies that restore anti-tumor immunity; however, only a small percentage of patients have been completely cured by ICI alone. Multiple approaches in combination with other modalities have been used to improve the efficacy of ICI therapy. Among conventional cancer treatments, radiotherapy or DNA damage-based chemotherapy is a promising candidate as a partner of ICI because DNA damage signaling potentially stimulates immune activities turning the tumor’s immune environment into hot tumors. Programmed death-ligand 1 (PD-L1) and human leukocyte antigen class I (HLA-I), which are immune ligands, regulate the balance of anti-tumor immunity in the tumor microenvironment. PD-L1 functions as a brake to suppress cytotoxic T cell activity, whereas HLA-I is an immune accelerator that promotes the downstream of the T cell signaling. Accumulating evidence has demonstrated that DNA damage enhances the presentation of HLA-I on the surface of damaged cells. However, it is unclear how signal transduction in DNA-damaged cells upregulates the presentation of HLA-I with antigens. Our recent study uncovered the mechanism underlying DNA damage-induced HLA-I presentation, which requires polypeptide synthesis through a pioneer round of translation. In this review, we summarize the latest overview of how DNA damage stimulates antigen production presented by HLA-I.

  • Genome maintenance Mechanisms at the Chromatin Level

    Hirotomo Takatsuka, Atsushi Shibata, Masaaki Umeda

    International Journal of Molecular Sciences （MDPI）  22 （ 19 ） 10384 2021年09月

    記事・総説・解説・論説等（学術雑誌）, 共著

    　概要を見る

    Genome integrity is constantly threatened by internal and external stressors, in both animals and plants. As plants are sessile, a variety of environment stressors can damage their DNA. In the nucleus, DNA twines around histone proteins to form the higher-order structure “chromatin”. Unraveling how chromatin transforms on sensing genotoxic stress is, thus, key to understanding plant strategies to cope with fluctuating environments. In recent years, accumulating evidence in plant research has suggested that chromatin plays a crucial role in protecting DNA from genotoxic stress in three ways: (1) changes in chromatin modifications around damaged sites enhance DNA repair by providing a scaffold and/or easy access to DNA repair machinery; (2) DNA damage triggers genome-wide alterations in chromatin modifications, globally modulating gene expression required for DNA damage response, such as stem cell death, cell-cycle arrest, and an early onset of endoreplication; and (3) condensed chromatin functions as a physical barrier against genotoxic stressors to protect DNA. In this review, we highlight the chromatin-level control of genome stability and compare the regulatory systems in plants and animals to find out unique mechanisms maintaining genome integrity under genotoxic stress.

  • ATM's Role in the Repair of DNA Double-Strand Breaks

    Atsushi Shibata, Penny A. Jeggo

    Genes （MDPI）  12 （ 9 ） 1370 2021年08月

    記事・総説・解説・論説等（学術雑誌）, 共著, 筆頭著者, 責任著者

  • Modulation of immune responses by DNA damage signaling

    Yuki Uchihara, Tiara Bunga Mayang Permata, Hiro Sato, Atsushi Shibata

    DNA Repair （Elsevier）  104   103135 2021年08月

    記事・総説・解説・論説等（学術雑誌）, 共著, 最終著者, 責任著者

    　概要を見る

    An accumulation of evidence indicates the importance of DNA damage signaling in modulating immune responses. Indeed, understanding the mechanism that underlies signal transduction originating from DNA damage is vital to overcoming refractory cancer, particularly when cancer immune therapy is applied in combination with DNA damage-dependent radio/chemotherapy. In addition, immune-associated responses to such signals can aggravate the symptoms of infections, allergies, autoimmune disease, and aging. In this review, we discuss how cells transduce signals, triggered by DNA damage, from their origins to neighboring cells and how this affects immune and inflammatory responses.

  • Canonical DNA non-homologous end-joining; capacity versus fidelity

    Atsushi Shibata, Penny A. Jeggo

    British Journal of Radiology （Oxford University Press）  93 （ 1115 ） 20190966 2020年11月

    記事・総説・解説・論説等（学術雑誌）, 共著, 筆頭著者

    　概要を見る

    The significance of canonical DNA non-homologous end-joining (c-NHEJ) for DNA double strand break (DSB) repair has increased from lower organisms to higher eukaryotes, and plays the predominant role in human cells. Ku, the c-NHEJ end-binding component, binds DSBs with high efficiency enabling c-NHEJ to be the first choice DSB repair pathway, although alternative pathways can ensue after regulated steps to remove Ku. Indeed, radiation-induced DSBs are repaired rapidly in human cells. However, an important question is the fidelity with which radiation-induced DSBs are repaired, which is essential for assessing any harmful impacts caused by radiation exposure. Indeed, is compromised fidelity a price we pay for high capacity repair. Two subpathways of c-NHEJ have been revealed; a fast process that does not require nucleases or significant chromatin changes and a slower process that necessitates resection factors, and potentially more significant chromatin changes at the DSB. Recent studies have also shown that DSBs within transcriptionally active regions are repaired by specialised mechanisms, and the response at such DSBs encompasses a process of transcriptional arrest. Here, we consider the limitations of c-NHEJ that might result in DSB misrepair. We consider the common IR-induced misrepair events and discuss how they might arise via the distinct subpathways of c-NHEJ.

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • DNA損傷により惹起されるゲノム変異非依存的な新規ネオアンチゲン発生機構の解明

    2023年06月
    -
    2025年03月

    科学研究費助成事業, 柴田 淳史, 挑戦的研究（萌芽）, 補助金,  研究代表者

    　研究概要を見る

    我々のこれまでの研究成果から、DNA損傷後のシグナル伝達が、転写及び翻訳の変化を引き起こし、非自己となる抗原（ネオアンチゲン）を産生しているという新たなモデルを考案している。そこで本研究では、「ゲノム変異非依存的なネオアンチゲン産生機構」の立証およびその分子機構解明を目的として、DNA損傷依存的な転写および翻訳開始点の変化を検出および解析する。DNA損傷という細胞に過度なストレスを与えた環境においては、従来の定説とは異なる抗原産生メカニズムが働くという新しい生命応答を示すことができ、当該分野における新たな概念を世界に先駆けて発信することができると考えている。

  • 酸化ストレスに対するミトコンドリア翻訳停滞解消システムの役割

    2023年04月
    -
    2026年03月

    科学研究費助成事業, 行木 信一, 柴田 淳史, 基盤研究(C), 未設定

    　研究概要を見る

    翻訳停滞とは，翻訳中にリボソームがmRNA上で停滞して蛋白質合成が滞る状態を指す。ミトコンドリアの翻訳系には，2種類の翻訳停滞解消因子「C12orf65」および「ICT1」が必ず存在するが，長らくC12orf65とICT1の機能的差異については不明であった。申請者は出芽酵母を用いた実験により，C12orf65が「リボソーム結合性抗生物質による翻訳停滞」の解消に必須であることを明らかにした。本研究では，ミトコンドリアにとって内在的リスク因子である酸化ストレスに着目し，酸化ストレスに対するミトコンドリア翻訳停滞解消システムの役割の解明を行う。

  • 人工ウィルスにより抗腫瘍免疫を起動する新規免疫療法の開発

    2023年04月
    -
    2026年03月

    科学研究費助成事業, 中島 菜花子, 長田 健介, 柴田 淳史, 基盤研究(C), 未設定

    　研究概要を見る

    本研究は、免疫から逃避している腫瘍に、抗腫瘍免疫を起動する遺伝子を導入し、惹起された免疫機構により腫瘍を排除する新規がん治療法の開発を目的としている。本研究では、全身投与が可能であり、定的に腫瘍に遺伝子を導入する人工ウィルス(非ウィルス型ベクター）を用い、腫瘍の免疫原性を高める遺伝子を腫瘍に強制発現させる。そして、人工ウィルスの有効性、すなわち腫瘍特異的遺伝子導入率・抗腫瘍免疫の賦活化・腫瘍増殖の抑制効果を検証する。本研究で提案する治療法は、全ての腫瘍において適応可能であり、従来の免疫療法との併用によりそれぞれの奏功の最大化も期待できる新規免疫療法である。

  • 非自己核酸が誘発するHLA提示およびISGs発現誘導を介した免疫惹起機構の研究

    2021年09月
    -
    2023年03月

    日本学術振興会, 科学研究費助成事業 学術変革領域研究(A), 柴田 淳史, 学術変革領域研究(A), 未設定

  • 全ゲノム領域に共通した正確なDNA修復を保証するDSB修復経路選択機構の研究

    2021年04月
    -
    2025年03月

    日本学術振興会, 科学研究費助成事業 基盤研究(B), 柴田 淳史, 山内 基弘, 宮成 悠介, 安原 崇哲, 山内 基弘, 宮成 悠介, 安原 崇哲, 基盤研究(B), 未設定

    　研究概要を見る

    放射線はヒト体内にあるDNAに対して様々な形状の損傷を与える。その多様なDNA損傷の中で、DNA二重鎖が同時に切断されるDNA二本鎖切断は最も重篤なDNA損傷の一つとされている。一方で人体は、傷ついたDNAを復元する「DNA修復」という機能を持つことから、正確にDNAを修復できるかどうかがその後の人体の運命決定に大きな影響を与える。本研究ではDNA修復の精度に関わる最重要分子である53BP1を対象に、その詳細な分子機構解明に挑戦する。人体がどのようにして正確なDNA修復を実現するか、その仕組みを明らかにすることで、放射線障害の低減に貢献することができると考えている。

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受賞 【 表示 ／ 非表示 】

  • 放射線影響研究 奨励賞

    2020年03月, 公益財団法人放射線影響協会

  • 放射線影響学会 奨励賞

    柴田 淳史, 2017年

  • 日本放射線影響学会第60回大会 優秀演題発表賞

    柴田 淳史, 2017年

  • 第24回 DNA複製・組換え・修復ワークショップ 若手発表賞

    柴田 淳史, 2017年

  • Poster prize

    柴田 淳史, 2012年, Joint British Association for Cancer Research-Gray Institute

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担当授業科目 【 表示 ／ 非表示 】

  • 課題研究（分子腫瘍薬学）

    2024年度

  • 演習（分子腫瘍薬学）

    2024年度

  • 卒業研究１（薬学科）

    2024年度

  • 英語演習（薬学科）

    2024年度

  • 病態薬学特論

    2024年度

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