Development of neuronal death inhibitor administration method by signal transduction imaging technology

• Project/Area Number: 18K16578
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: The University of Tokyo
• Principal Investigator: Karasawa Yasuaki 東京大学, 大学院理学系研究科(理学部), 客員共同研究員 (70812957)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 神経細胞死 / シグナル伝達 / ライブセルイメージ / 時系列データ解析 / システム生物学 / 数理モデル / 再生治療 / 細胞療法 / 酸化ストレス / MAP kinase / 数理モデル解析 / 時系列データ / 再生医療 / 骨髄由来間葉系間質細胞 / リハビリテーション / 糖代謝、脂質代謝 / FRETプローブ / 相互情報量 / 糖代謝 / MAPキナーゼ / 細胞死 / 脳・神経 / MAP Kinase

Outline of Final Research Achievements

By incorporating a fluorescent biosensor (FRET probe) into hippocampus-derived neurons (HT22 cells), we established an experimental model with good temporal and spatial resolution that can visualize and quantify JNK activity at one-minute intervals for each cell. We developed an auto-tracking program that can automatically detect, track, and quantify cell nuclei from live cell imaging data. We clarified the relationship between the precedence of JNK activation and subsequent cell death, and confirmed the reversibility of JNK activation. We also advanced research in the field of system biology such as time-series analysis, mathematical model analysis, mutual information analysis, and research on regenerative therapy using stem cells.

Academic Significance and Societal Importance of the Research Achievements

酸化ストレスから細胞死へ至るシグナル伝達経路にはＭＡＰキナーゼの活性化が重要な役割を演じており、治療のターゲットの一つと考えられている。酸化ストレスによる神経細胞死は、脳梗塞をはじめとする急性脳障害だけでなく認知症などの慢性脳障害の原因の一つとみなされており、新規治療薬の開発が期待されている。本研究で開発した画像解析システムは、移動して分裂する細胞の核を自動で追随し、蛍光強度を定量化する手法で、他の浮遊細胞にも適応可能であり、汎用性は非常に高い。研究成果は、培養細胞の基礎的なものから、ヒトを対象としたシステム生物学、解析手法、そして幹細胞移植の治験へと、基礎から理論、臨床への橋渡しとなった。

Research Products

• [Int'l Joint Research] VIB-KU Leuven Center for Cancer Biology/Leuven Cancer Institute (LKI)(ベルギー)
• [Int'l Joint Research] TIGEM(イタリア)
• [Int'l Joint Research] Hunan University(中国)
• [Int'l Joint Research] Hopp Children’s Cancer Center (KiTZ)/German Cancer Research Center (DKFZ),/Heidelberg University Hospital(ドイツ)
• [Int'l Joint Research] ETH Zurich(スイス)
• [Journal Article] Features extracted using tensor decomposition reflect the biological features of the temporal patterns of human blood multimodal metabolome (2023)
  • Author(s): Fujita Suguru、Karasawa Yasuaki、Hironaka Ken-ichi、Taguchi Y.-h.、Kuroda Shinya
  • Journal Title: PLOS ONE Volume: 18 Issue: 2 Pages: e0281594-e0281594
  • DOI: 10.1371/journal.pone.0281594
  • Peer Reviewed / Open Access
• [Journal Article] Recurrent glioblastoma metastatic to the lumbar vertebra: A case report and literature review: Surgical oncology (2023)
  • Author(s): Matsuhashi Ako、Tanaka Shota、Takami Hirokazu、Nomura Masashi、Ikemura Masako、Matsubayashi Yoshitaka、et al.
  • Journal Title: Frontiers in Oncology Volume: 13 Pages: 1101552-1101552
  • DOI: 10.3389/fonc.2023.1101552
  • Peer Reviewed / Open Access
• [Journal Article] Four features of temporal patterns characterize similarity among individuals and molecules by glucose ingestion in humans (2022)
  • Author(s): Fujita Suguru、Karasawa Yasuaki、Fujii Masashi、Hironaka Ken-ichi、Uda Shinsuke、Kubota Hiroyuki、Inoue Hiroshi、Sumitomo Yohei、Hirayama Akiyoshi、Soga Tomoyoshi、Kuroda Shinya
  • Journal Title: npj Systems Biology and Applications Volume: 8 Issue: 1 Pages: 6-6
  • DOI: 10.1038/s41540-022-00213-0
  • Peer Reviewed / Open Access
• [Journal Article] Fat Induces Glucose Metabolism in Nontransformed Liver Cells and Promotes Liver Tumorigenesis (2021)
  • Author(s): L. A. Broadfield, J. A. G. Duarte, R. Schmieder, D. Broekaert, K. Veys, M. Planque, K. Vriens, Y. Karasawa, F. Napolitano, S. Fujita, M. Fujii, M. Eto, B. Holvoet, R. Vangoitsenhoven, J. Fernandez-Garcia, J. van Elsen, J. Dehairs, J. Zeng, J. Dooley, R. Alba Rubio, J. van Pelt et al.
  • Journal Title: Cancer Research Volume: 81 Issue: 8 Pages: 1988-2001
  • DOI: 10.1158/0008-5472.can-20-1954
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell Therapy for Chronic TBI (2021)
  • Author(s): Kawabori Masahito, Imai Hideaki, Zinkevych Iaroslav, McAllister Peter, Steinberg Gary, Frishberg Benjamin , Chida Dai, Kaneko Takehiko, Karasawa Yasuaki, Paadre Susan, Nejadnik Bijan, Bates Damien, Stonehouse Anthony, Richardson Mark, Okonkwo David, et al.
  • Journal Title: Neurology Volume: 96 Issue: 8
  • DOI: 10.1212/wnl.0000000000011450
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Single-Cell Information Analysis Reveals That Skeletal Muscles Incorporate Cell-to-Cell Variability as Information Not Noise (2020)
  • Author(s): Wada Takumi、Hironaka Ken-ichi、Wataya Mitsutaka、Fujii Masashi、Eto Miki、Uda Shinsuke、Hoshino Daisuke、Kunida Katsuyuki、Inoue Haruki、Kubota Hiroyuki、Takizawa Tsuguto、Karasawa Yasuaki、Nakatomi Hirofumi、Saito Nobuhito、Hamaguchi Hiroki、Furuichi Yasuro、Manabe Yasuko、Fujii Nobuharu L.、Kuroda Shinya
  • Journal Title: Cell Reports Volume: 32 Issue: 9 Pages: 108051-108051
  • DOI: 10.1016/j.celrep.2020.108051
  • Peer Reviewed / Open Access
• [Journal Article] Effects of low-carbohydrate diet and resistance exercise training on physical characteristics and concentrations of plasma metabolites and hormones (2019)
  • Author(s): Ito Sho、Karasawa Yasuaki、Hoshino Daisuke、Fujii Masashi、Eto Miki、Tsuru Junya、Kashiwado Chieko、Kuroda Shinya
  • Journal Title: Japanese Journal of Physical Fitness and Sports Medicine Volume: 68 Issue: 3 Pages: 223-227
  • DOI: 10.7600/jspfsm.68.223
  • NAID: 130007650932
  • ISSN: 0039-906X, 1881-4751
  • Year and Date: 2019-06-01
  • Peer Reviewed / Open Access
• [Journal Article] Logical design of oral glucose ingestion pattern minimizing blood glucose in humans. (2019)
  • Author(s): Fujii M, Murakami Y, Karasawa Y, Sumitomo Y, Fujita S, Koyama M, Uda S, Kubota H, Inoue H, Konishi K, Oba S, Ishii S, Kuroda S.
  • Journal Title: NPJ Syst Biol Appl. Volume: 5 Issue: 1 Pages: 31-31
  • DOI: 10.1038/s41540-019-0108-1
  • NAID: 120006939199
  • Peer Reviewed / Open Access
• [Journal Article] Effects of low-carbohydrate diet and resistance exercise training on physical characteristics and concentrations of plasma metabolites and hormones (2019)
  • Author(s): Sho Ito, Yasuaki Karasawa, Daisuke Hoshino, Masashi Fujii, Miki Eto, Junya Tsuru, Chieko Kashiwado, Shinya Kuroda
  • Journal Title: 体力科学 Volume: 68
  • NAID: 130007650932
  • Peer Reviewed / Open Access
• [Journal Article] 症例報告 音韻失読･音韻失書を呈した1例-語の音読と書き取りにおける障害の機序 (2018)
  • Author(s): 兼岡 麻子, 井口 はるひ, 唐沢 康暉 , 芳賀 信彦
  • Journal Title: 言語聴覚研究 Volume: 15 Issue: 4 Pages: 342-350
  • DOI: 10.11477/mf.6001200198
  • NAID: 40021805714
  • ISSN: 1349-5828
  • Year and Date: 2018-12-15
  • Peer Reviewed / Open Access
• [Presentation] 慢性期頭部外傷患者に対する他家骨髄由来間葉系間質細胞（SB623）の脳内投与の治験成績_第二相STEMTRA試験 (2022)
  • Author(s): 唐沢 康暉 篠田裕介、川堀真人、池田聡、生駒一憲、末永潤、中村健 安原隆雄、堅山佳美、濱田全紀、千田大、千田益生
  • Organizer: 第59回日本リハビリテーション医学会学術集会
• [Presentation] 骨髄由来間葉系幹細胞SB623の脳内投与による慢性期頭部外傷患者のNeuro-QOLへの効果_STEMTRA試験(事後解析) (2022)
  • Author(s): 唐沢 康暉 篠田裕介、川堀真人、池田聡、生駒一憲、末永潤、中村健 安原隆雄、堅山佳美、濱田全紀、千田大、千田益生
  • Organizer: 第6回日本リハビリテーション医学会秋季学術集会
• [Presentation] 慢性期頭部外傷患者に対する他家骨髄由来間葉系間質細胞(SB623)の脳内投与の治験成績_第二相STEMTRA試験 (2022)
  • Author(s): 唐沢 康暉、篠田裕介、川堀真人、池田聡、生駒一憲、末永潤、中村健 安原隆雄、堅山佳美、千田益生、濱田全紀、千田大
  • Organizer: 第59回日本リハビリテーション医学会学術集会
• [Presentation] 中枢神経への幹細胞移植治療における有効性評価 ～リハビリテーション科と臨床研究～ (2020)
  • Author(s): 唐沢 康暉, 今井 英明, 横田 一彦, 奈良 篤史, 辛 正廣, 篠田 裕介, 芳賀 信彦,齊藤 延人
  • Organizer: 第79回 日本脳神経外科学会 学術総会
• [Presentation] Rehabilitation For Central Nervous System Regenerative Cell Transplantation. (2019)
  • Author(s): Karasawa Y、Imai H、Shinoda Y、Haga N
  • Organizer: 13th International Society of Physical and Rehabilitation Medicine
  • Int'l Joint Research
• [Presentation] Safety and Clinical Outcomes in Traumatic Brain Injury Patients: Interim Analysis of the STEMTRA Trial. (Anchor presentation of AANS 2019) (2019)
  • Author(s): Yasuaki Karasawa、Hideaki Imai、David O. Okonkwo、Peter McAllister、Masahito Kawabori、Jefferson W. Chen、Benjamin M. Frishberg、Takao Yasuhara、Jun Suenaga、Hajime Nakamura、Damien Bates、Takehiko Kaneko
  • Organizer: 第20回日本分子脳神経外科学会
• [Presentation] 脳神経領域における再生医療・細胞療法 (2019)
  • Author(s): 唐沢 康暉
  • Organizer: 第17回日本神経理学療法学会学術大会
  • Invited
• [Presentation] 中枢神経への幹細胞移植治療における リハビリテーションの役割 (2019)
  • Author(s): 唐沢康暉、今井英明、横田一彦、奈良篤史、辛正廣、篠田裕介、芳賀信彦、齊藤延人
  • Organizer: 第78回日本脳神経外科学会総会
• [Presentation] Safety and Clinical Outcomes in Traumatic Brain Injury Patients: Interim Analysis of the STEMTRA Trial in Asian Subpopulation (2019)
  • Author(s): Takao Yasuhara, Tatsuya Sasaki, David O. Okonkwo, Masahito Kawabori, Hideaki Imai, Jun Suenaga, Hajime Nakamura, Yasuaki Karasawa, Takehiko Kaneko, Damien Bates
  • Organizer: WFNS Congress Beijing 2019
  • Int'l Joint Research
• [Presentation] Fluorescence Resonance Energy Transfer (FRET) based Quantitative Analysis of c-jun N-terminal kinase (JNK) in Oxidative Stress-induced Cell Death (2019)
  • Author(s): Yasuaki Karasawa, Hideaki Imai, Nobuhito Saito
  • Organizer: BRAIN & BRAIN PET2019.
  • Int'l Joint Research
• [Presentation] Rehabilitation for Central Nervous System Regenerative Cell Transplantation. (2019)
  • Author(s): Yasuaki Karasawa, Hideaki Imai, Nobuhiko Haga
  • Organizer: 13th International Society of Physical and Rehabilitation Medicine World Congress
  • Int'l Joint Research
• [Presentation] 他家間葉系幹細胞由来の細胞治療薬移植による頭部外傷治療 (2018)
  • Author(s): 今井 英明, 唐沢 康暉, 長谷川 洋敬, 辛 正廣, 齊藤 延人
  • Organizer: 日本脳神経外科学会第77回学術総会
  • Invited
• [Presentation] 糖摂取後の網羅的なヒト血中分子濃度の時間変動解析 (2018)
  • Author(s): 唐沢康暉, 藤井雅史, 藤田卓,宇田新介, 大橋郁, 住友洋平, 平山明由, 曽我朋義, 黒田真也
  • Organizer: 日本生化学会大会
• [Presentation] Time-series analysis of metabolic responsiveness to the oral glucose ingestion (2018)
  • Author(s): 唐沢康暉, 藤田卓,藤井雅史, 宇田新介, 大橋郁, 平山明由, 曽我朋義, 黒田真也
  • Organizer: 日本生物物理学会2018年年会
• [Remarks] 経口糖摂取に応答するヒト血中分子の時間パターン
  • URL: http://kurodalab.bs.s.u-tokyo.ac.jp/ja/research/#human
• [Remarks] 細胞のばらつきはノイズではなく情報である
  • URL: https://www.s.u-tokyo.ac.jp/ja/info/6977/