Investigation of the mechanism of ischemic brain injury in extremely preterm infants

• Project/Area Number: 15K09723
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Embryonic/Neonatal medicine
• Research Institution: Keio University
• Principal Investigator: Deguchi Kimiko 慶應義塾大学, 医学部(信濃町), 講師(非常勤) (50227542)
• Co-Investigator(Kenkyū-buntansha): 久保 健一郎 慶應義塾大学, 医学部(信濃町), 講師 (20348791)
• Co-Investigator(Renkei-kenkyūsha): INOUE Ken 国立精神, 神経センター・神経研・疾病二部, 室長 (30392418)
• Research Collaborator: ISHII Kazuhiro
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 虚血 / 脳障害 / 神経細胞移動 / マウスモデル / 認知機能 / 大脳皮質 / 層構造 / 治療法開発 / 超早産児 / 虚血性脳障害 / モデルマウス / 認知機能障害 / 作業記憶 / DREDDシステム / 発達障害

Outline of Final Research Achievements

Many extremely preterm infants (EPIs) subsequently develop cognitive impairment of unknown etiology. We observed fewer neural progenitors and larger numbers of ectopic neurons in the white matter (WM) of human EPI brains and hypothesized that EPIs develop cognitive dysfunction because of altered neuronal generation and migration. To test our hypothesis we produced ischemic brain damage in mouse embryos by occluding maternal uterine arteries. The mice showed decreased proliferation of neuronal progenitors, delayed neuronal migration, and ectopic neurons in the WM. Similar to human EPIs the surviving mice exhibited abnormal cognitive function. Maternal hypothermia during the arterial occlusion period mitigated the neurodevelopmental damage. These findings supported our hypothesis that altered neuronal generation and migration underlie the serious risk of subsequent cognitive impairment of EPIs.

Research Products

• [Int'l Joint Research] Baylor College of Medicine(米国)
• [Int'l Joint Research] Baylor College of Medicine(米国)
• [Journal Article] Association of impaired neuronal migration with cognitive deficits in extremely preterm infants. (2017)
  • Author(s): Kubo, K.I., Deguchi, K., Nagai, T,, Ito, Y., Yoshida, K., Endo, T., Benner, S., Shan, W., Kitazawa, A., Aramaki, M., Ishii, K., Shin, M., Matsunaga, Y., Hayashi, K., Kakeyama, M., Tohyama, C., Tanaka, K.F., Tanaka, K., Takashima, S., Nakayama, M.
  • Journal Title: JCI Insight. Volume: 2 Issue: 10 Pages: 88609-88609
  • DOI: 10.1172/jci.insight.88609
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of impaired neuronal migration with cognitive deficits in extremely preterm infants (2017)
  • Author(s): K. Kubo, K. Deguchi, T. Nagai, Y. Ito, K. Yoshida, T. Endo, S. Benner, W.Shan, A.o Kitazawa, M. Aramaki, K. Ishii, M. Shin, Y. Matsunaga, K. Hayashi, M. Kakeyama, C. Tohyama, K. F. Tanaka, K. Tanaka, S. Takashima, M. Nakayama, M. Itoh, Y. Hirata, B. Antalffy, D. D. Armstrong, K.Yamada, K. Inoue, and K. Nakajima
  • Journal Title: JCI Insight Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ApoER2 controls not only neuronal migration in the intermediate zone, but also termination of migration in the developing cerebral cortex. (2017)
  • Author(s): Yuki Hirota, Ken-ichiro Kubo, Takahiro Fujino, Tokuo T. Yamamoto, and Kazunori Nakajima
  • Journal Title: Cereb. Cortex Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse (2017)
  • Author(s): Eiki Kimura, Ken-ichiro Kubo, Toshihiro Endo, Kazunori Nakajima, Masaki Kakeyama, and Chiharu Tohyama
  • Journal Title: The Journal of Toxicological Sciences Volume: 42 Issue: 1 Pages: 25-30
  • DOI: 10.2131/jts.42.25
  • NAID: 130005286645
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Reelin transiently promotes N-cadherin-dependent neuronal adhesion during mouse cortical development (2017)
  • Author(s): Yuki Matsunaga, Mariko Noda, Hideki Murakawa, Kanehiro Hayashi, Arata Nagasaka, Seika Inoue, Takaki Miyata, Takashi Miura, Ken-ichiro Kubo, and Kazunori Nakajima
  • Journal Title: Proc. Natl. Acad. Sci. U.S.A. Volume: 114 Issue: 8 Pages: 2048-2053
  • DOI: 10.1073/pnas.1615215114
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Reelin and neuropsychiatric disorders (2016)
  • Author(s): Kazuhiro Ishii, Ken-ichiro Kubo, and Kazunori Nakajima
  • Journal Title: Front. Cell. Neurosci. Volume: 10
  • DOI: 10.3389/fncel.2016.00229
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cellular dynamics of neuronal migration in the hippocampus. (2015)
  • Author(s): Kanehiro Hayashi, Ken-ichiro Kubo, Ayako Kitazawa, and Kazunori Nakajima
  • Journal Title: Front. Neurosci. Volume: 9 Pages: 135-135
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neuronal heterotopias affect the activities of distant brain areas and lead to behavioral deficits. (2015)
  • Author(s): Kazuhiro Ishii, Ken-ichiro Kubo, Toshihiro Endo, Keitaro Yoshida, Seico Benner,Yukiko Ito, Hidenori Aizawa, Michihiko Aramaki, Akihiro Yamanaka, Kohichi Tanaka, Norio Takata, Kenji F. Tanaka, Masaru Mimura, Chiharu Tohyama, Masaki Kakeyama, and Kazunori Nakajima.
  • Journal Title: J. Neurosci. Volume: 35 (36) Pages: 2432-12445
  • Peer Reviewed / Open Access
• [Presentation] Improvement of cognitive deficits observed in a mouse model of extremely preterm infants with brain injuries (2018)
  • Author(s): Ken-ichiro Kubo, Kimiko Deguchi, Debabrata Hazra, Satoshi Yoshinaga, Ayako Kitazawa, Minkyung Shin, Keitaro Yoshida, Kenji F. Tanaka, Ken Inoue, and Kazunori Nakajima
  • Organizer: 第123回日本解剖学会総会・全国学術集会
• [Presentation] 超早産児脳障害のモデルマウス脳における組織構築の解析 (2017)
  • Author(s): 久保健一郎、出口貴美子、北澤彩子、石井一裕、シン ミンギョン、高嶋幸男、中山雅弘、伊藤雅之、井上健、仲嶋一範
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎大学坂本キャンパス、長崎市(長崎県)
  • Year and Date: 2017-03-28
• [Presentation] Analysis of cortical development in a newly established mouse model of extremely preterm infants with brain injuries (2017)
  • Author(s): Ken-ichiro Kubo, Kimiko Deguchi, et al.
  • Organizer: Society for Neuroscience, Neuroscience 2017 meeting
  • Int'l Joint Research
• [Presentation] 超早産児に生じる脳障害のマウスモデル作成の試み (2017)
  • Author(s): 久保健一郎、出口貴美子、永井拓、シャン ウェイ、北澤彩子、荒巻道彦、石井一裕、シン ミンギョン、高嶋幸男、中山雅弘、伊藤雅之、アンタルフィ バーバラ、アームストロング ダーナ、山田清文、井上健、仲嶋一範
  • Organizer: 第52回TOKYOニューロサイエンス研究会
• [Presentation] マウスにおける神経発達障害モデルの作成とその解析 (2017)
  • Author(s): 久保健一郎、出口貴美子、石井一裕、井上健、仲嶋一範
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会合同年会
  • Invited
• [Presentation] 認知機能障害を伴うマウスモデルの作成とその脳における細胞構築の解析 (2017)
  • Author(s): Ken-ichiro Kubo, Kimiko Deguchi, Kazuhiro Ishii, Ken Inoue, and Kazunori Nakajima
  • Organizer: 第60回日本神経化学会大会
• [Presentation] Establishment of a mouse model of extremely preterm infants with brain injuries and analysis of neuronal migration (2017)
  • Author(s): Ken-ichiro Kubo, Kimiko Deguchi, Taku Nagai, Keitaro Yoshida, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Shin Minkyung, Kenji F. Tanaka, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Yukio Hirata, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue, and Kazunori Nakajima
  • Organizer: 第40回日本神経科学大会
• [Presentation] Abnormal neuronal migration with ischemic brain injuries in extremely preterm infants underlies subsequent cognitive impairment (2017)
  • Author(s): Kimiko Deguchi, Ken-ichiro Kubo, Kazunori Nakajima, and Ken Inoue
  • Organizer: 12th European Paediatric Neurology Society (EPNS) Congress
  • Int'l Joint Research
• [Presentation] Why does cognitive impairment frequently develop later in extremely preterm infants (2016)
  • Author(s): Ken-ichiro Kubo, Kimiko Deguchi, Taku Nagai, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Shin Minkyung, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue, and Kazunori Nakajima
  • Organizer: Cell Symposia: Big Questions in Neuroscience
  • Place of Presentation: Paradise Point Resort & Spa,San Diego, California, U.S.A.
  • Year and Date: 2016-11-10
  • Int'l Joint Research
• [Presentation] 環境要因としての虚血ストレスが大脳皮質の発達に与える影響 (2016)
  • Author(s): 久保健一郎、出口貴美子、井澤栄一、井上健、仲嶋一範
  • Organizer: フォーラム2016：衛生薬学・環境トキシコロジー
  • Place of Presentation: 昭和大学旗の台キャンパス、品川区(東京都）
  • Year and Date: 2016-09-10
  • Invited
• [Presentation] Reelin coupled with myelin may play a role in long term maintenance of myelin (2016)
  • Author(s): Kimiko Deguchi，Takao Honda, Ken-ichiro Kubo, Kazunori Nakajima,and Ken Inoue
  • Organizer: 第58回日本小児神経学会学術集会
  • Place of Presentation: 京王プラザホテル新宿、新宿(東京都）
  • Year and Date: 2016-06-03
• [Presentation] Reelin coupled with myelin may play a role in long-term maintenance of myelin (2016)
  • Author(s): Kimiko Deguchi, Takao Honda, Ken-ichiro Kubo, Kazunori Nakajima, and Ken Inoue
  • Organizer: 21st Biennial Meeting of the International Society for Developmental Neuroscience (ISDN2016)
  • Place of Presentation: Antibes-Juan les Pins, France
  • Year and Date: 2016-05-11
  • Int'l Joint Research
• [Presentation] Functional screening of the candidate genes involved in the expansion of the subventricular zone in primates using mouse embryos (2016)
  • Author(s): Hidenori Tabata, Tsuyoshi Hachiya, Koh-ichi Nagata, Yasubumi Sakakibara, and Kazunori Nakajima
  • Organizer: 新学術領域研究「神経細胞の多様性と大脳新皮質の構築」第3回国際シンポジウム「Neocortical Organization 3」
  • Place of Presentation: 東京大学小柴ホール(東京都文京区)
  • Year and Date: 2016-02-11
  • Int'l Joint Research
• [Presentation] 異所性灰白質は離れた脳部位の神経活動に影響を与えて行動の異常を引き起こす (2015)
  • Author(s): 久保健一郎、石井一裕、遠藤俊裕、吉田慶太朗、ベナー聖子、伊藤亨子、相澤秀紀、荒巻道彦、山中章弘、田中光一、高田則雄、田中謙二、三村將、遠山千春、掛山正心、仲嶋一範
  • Organizer: 日本解剖学会関東支部 第103回学術集会
  • Place of Presentation: 慶應義塾大学日吉キャンパス(神奈川県横浜市)
  • Year and Date: 2015-11-07
• [Presentation] Application of the in utero electroporation technique to the study of the pathological mechanism of focal heterotopias in the brain (2015)
  • Author(s): Ken-ichiro Kubo, Kazuhiro Ishii, Toshihiro Endo, Keitaro Yoshida, Seico Benner, Yukiko Ito, Hidenori Aizawa, Michihiko Aramaki, Akihiro Yamanaka, Kohichi Tanaka, Norio Takata, Kenji F. Tanaka, Masaru Mimura, Chiharu Tohyama, Masaki Kakeyama, and Kazunori Nakajima
  • Organizer: Cell Symposia
  • Place of Presentation: Chicago(U.S.A.)
  • Year and Date: 2015-10-15
  • Int'l Joint Research
• [Remarks] 超早産児に生じる認知機能障害に脳の神経細胞の移動障害が関与－その予防・治療法の新規開発に期待－
  • URL: https://www.keio.ac.jp/ja/press-releases/2017/5/19/28-20697/