Investigation of pathogenesis of mesial temporal epilepsy using monogenic mouse model

• Project/Area Number: 25460493
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya University
• Principal Investigator: Asai Masato 名古屋大学, 医学(系)研究科(研究院), 特任講師 (70543536)
• Co-Investigator(Kenkyū-buntansha): ENOMOTO ATSUSHI 名古屋大学, 大学院医学系研究科, 准教授 (20432255) ; ASAI NAOYA 名古屋大学, 大学院医学系研究科, 准教授 (80273233)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 側頭葉てんかん / 海馬硬化 / 動物モデル / ノックアウトマウス / 全般化発作 / 感覚辺縁系過剰結合 / モデルマウス / 実験病理学 / てんかんビデオモニタリング / 睡眠てんかん

Outline of Final Research Achievements

Epilepsy is a chronic disorder characterized by recurrent seizures (by WHO's definition). The seizures are caused by sudden, usually brief, excessive electrical discharges in a group of neurons. However, the forming conditions of excessive electrical discharges are completely unknown. Mesial-temporal lobe epilepsy (MTLE), which is originated from hippocampus, is the most common form of adult epilepsy. We developed and patented monogenic MTLE mouse by ablating Girdin gene, which keeps exhibiting generalized tonic-clonic seizures and lower-level seizures for life (approximately two years) without any electrical- nor pharmacological induction. We also identified human patients in a consanguineous family with early onset epileptic seizures, caused by loss-of-function mutation in human Girdin gene (BRAIN 2016). By inferring forming conditions of excessive electrical discharges from the putative functions of Girdin protein, we proposed a new model to explain universal forms of epilepsy.

Research Products

• [Int'l Joint Research] University of Cambridge/Cambridge Institute for Medical Research(英国)
• [Int'l Joint Research] Universita degli Studi di Trieste/Dip. Scienze della Vita(イタリア)
• [Int'l Joint Research] Harvard University/Boston Children's Hospital(米国)
• [Journal Article] CCDC88A mutations cause PEHO-like syndrome in humans and mouse. (2016)
  • Author(s): Nahorski MS, Asai M, Wakeling E, Parker A, Asai N, Canham N, Holder SE, Chen YC, Dyer J, Brady AF, Takahashi M, Woods CG.
  • Journal Title: Brain. Volume: 139 Issue: 4 Pages: 1036-1044
  • DOI: 10.1093/brain/aww014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of Meflin as a Potential Marker for Mesenchymal Stromal Cells (2016)
  • Author(s): Maeda K, Enomoto A, Hara A, Asai N, Kobayashi T, Horinouchi A, Maruyama S, Ishikawa Y, Nishiyama T, Kiyoi H, Kato T, Ando K, Weng L, Mii S, Asai M, Mizutani Y, Watanabe O, Hirooka Y, Goto H, Takahashi M
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 22288-22288
  • DOI: 10.1038/srep22288
  • Peer Reviewed / Open Access
• [Journal Article] Potential involvement of kinesin-1 in the regulation of subcellular localization of Girdin (2015)
  • Author(s): Aya Muramatsu, Atsushi Enomoto, Takuya Kato, Liang Weng, Keisuke Kuroda, Naoya Asai, Masato Asai, Shinji Mii, Masahide Takahashia
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 463 Issue: 4 Pages: 999-1005
  • DOI: 10.1016/j.bbrc.2015.06.049
  • Peer Reviewed / Open Access
• [Journal Article] A role for Daple in non-canonical Wnt signaling during gastric cancer invasion and metastasis (2015)
  • Author(s): Hosne Ara, Maki Takagishi, Atsushi Enomoto, Masato Asai, Kaori Ushida, Naoya Asai, Yoshie Shimoyama, Kozo Kaibuchi, Yasuhiro Kodera and Masahide Takahashi.
  • Journal Title: Cancer Science Volume: 107 Issue: 2 Pages: 133-139
  • DOI: 10.1111/cas.12848
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury (2015)
  • Author(s): Nakano T, Kotani T, Mano Y, Tsuda H, Imai K, Ushida T, Li H, Miki R, Sumigama S, Sato Y, Iwase A, Hirakawa A, Asai M, Toyokuni S, Kikkawa F.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 57 Issue: 3 Pages: 178-182
  • DOI: 10.3164/jcbn.15-90
  • NAID: 130005106454
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Girdin is phosphorylated on tyrosine 1798 when associated with structures required for migration (2015)
  • Author(s): Kenji Omori, Masato Asai, Daisuke Kuga, Kaori Ushida, Tetsuya Izuchi, Shinji Mii, Atsushi Enomoto, Naoya Asai, Masato Nagino, Masahide Takahashi
  • Journal Title: Biochem. Biopys. Res. Commun. Volume: 458 Issue: 4 Pages: 934-940
  • DOI: 10.1016/j.bbrc.2015.02.065
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells. (2014)
  • Author(s): Niimi K, Murakumo Y, Watanabe N, Kato T, Mii S, Enomoto A, Asai M, Asai N, Yamamoto E, Kajiyama H, Shibata K, Kikkawa F, Takahashi M.
  • Journal Title: Cancer Sci. Volume: 105 Issue: 5 Pages: 545-52
  • DOI: 10.1111/cas.12390
  • Peer Reviewed / Open Access
• [Journal Article] TRIM27/MRTF-B-Dependent Integrin β1 Expression Defines Leading Cells in Cancer Cell Collectives. (2014)
  • Author(s): Takuya Kato, Atsushi Enomoto, Takashi Watanabe, Hisashi Haga, Sumire Ishida, Yuji Kondo, Koichi Furukawa, Takeshi Urano, Shinji Mii, Liang Weng, Maki Ishida-Takagishi, Masato Asai, Naoya Asai, Kozo Kaibuchi, Yoshiki Murakumo, Masahide Takahashi.
  • Journal Title: Cell reports. Volume: 7 Issue: 4 Pages: 1156-1167
  • DOI: 10.1016/j.celrep.2014.03.068
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of cargo-selective endocytosis by dynamin 2 GTPase-activating protein girdin. (2014)
  • Author(s): Liang Weng, Atsushi Enomoto, Hiroshi Miyoshi, Kiyofumi Takahashi, Naoya Asai, Nobuhiro Morone, Ping Jiang, Jian An, Takuya Kato, Keisuke Kuroda, Takashi Watanabe, Masato Asai, Maki Ishida-Takagishi, Yoshiki Murakumo, Hideki Nakashima, Kozo Kaibuchi and Masahide Takahashi.
  • Journal Title: EMBO Journal. Volume: 33 Issue: 18 Pages: 2098-2112
  • DOI: 10.15252/embj.201488289
  • Peer Reviewed / Open Access
• [Journal Article] Girdin phosphorylation is crucial for synaptic plasticity and memory: A potential role in the interaction of BDNF/TrkB/Akt signaling with NMDA receptor (2014)
  • Author(s): Tsuyoshi Nakai, Taku Nagai, Motoki Tanaka, Norimichi Itoh, Naoya Asai, Atsushi Enomoto, Masato Asai, Shinnnosuke Yamada, Ali Bin Saifullah, Masahiro Sokabe, Masahide Takahashi, Kiyofumi Yamada
  • Journal Title: The Journal of Neuroscience Volume: 34 Issue: 45 Pages: 14995-15008
  • DOI: 10.1523/jneurosci.2228-14.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Detection of a Soluble Form of CD109 in Serum of CD109 Transgenic and Tumor Xenografted Mice. (2014)
  • Author(s): Sakakura H, Murakumo Y, Mii S, Hagiwara S, Kato T, Asai M, Hoshino A, Yamamoto N, Sobue S, Ichihara M, Ueda M, Takahashi M.
  • Journal Title: PLoS One Volume: 9 Issue: 1 Pages: e83385-e83385
  • DOI: 10.1371/journal.pone.0083385
  • Peer Reviewed
• [Journal Article] Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. (2013)
  • Author(s): Asai M, Ramachandrappa S, Joachim M, Shen Y, Zhang R, Nuthalapati N, Ramanathan V, Strochlic DE, Ferket P, Linhart K, Ho C, Novoselova TV, Garg S, Ridderstråle M, Marcus C, Hirschhorn JN, Keogh JM, O'Rahilly S, Chan LF, Clark AJ, Farooqi IS, Majzoub JA.
  • Journal Title: Science Volume: 341 Issue: 6143 Pages: 275-278
  • DOI: 10.1126/science.1233000
  • Peer Reviewed
• [Journal Article] The REV7 subunit of DNA polymerase ζ is essential for primordial germ cell maintenance in the mouse. (2013)
  • Author(s): Watanabe, N., Mii, S., Asai, N., Asai, M., Niimi, K., Ushida, K., Kato, T., Enomoto, A., Ishii, H., Takahashi, M., Murakumo, Y.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 15 Pages: 10459-10471
  • DOI: 10.1074/jbc.m112.421966
  • Peer Reviewed
• [Presentation] 創薬を目的とした高品質の側頭葉てんかんマウスモデル (2016)
  • Author(s): 浅井真人
  • Organizer: 中部地区医療・バイオ系シーズ発表会
  • Place of Presentation: 名古屋市中小企業振興会館吹上ホール（愛知県名古屋市）
  • Year and Date: 2016-02-04
• [Presentation] メラノコルチン２受容体付属タンパク２（MRAP2）の機能喪失は哺乳類の肥満と関連する (2015)
  • Author(s): 浅井真人
  • Organizer: 第４９回日本小児内分泌学会学術集会
  • Place of Presentation: タワーホール船堀（東京都江戸川区）
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] 遺伝子Xのノックアウトマウス 理想的な内側側頭葉てんかんモデルマウス (2015)
  • Author(s): 浅井真人
  • Organizer: DSANJ疾患別商談会（中枢神経系疾患領域）
  • Place of Presentation: 大阪産業創造館（大阪府大阪市）
  • Year and Date: 2015-08-28
• [Presentation] 哺乳類消化管タフト細胞とアノイキスに陥った吸収上皮の同一性 (2015)
  • Author(s): 陸大輔 浅井真人 浅井直也 榎本篤 梛野正人 高橋雅英
  • Organizer: 第104回 日本病理学会総会
  • Place of Presentation: 愛知県名古屋市 名古屋国際会議場
• [Presentation] Mrap2遺伝子変異と肥満 (2014)
  • Author(s): 浅井真人
  • Organizer: 第41回 日本神経内分泌学会学術集会
  • Place of Presentation: 東京都千代田区 都道府県会館
  • Invited
• [Presentation] Phosphorylation of Girdin in Colorectal Cancer (2013)
  • Author(s): 大森健治、浅井真人、榎本篤、浅井直也、梛野正人、高橋 雅英
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜 横浜市
  • Year and Date: 2013-10-03
• [Presentation] リン酸化Girdin特異的抗体の作製とマウス脳における組織学的検討 (2013)
  • Author(s): 浅井真人
  • Organizer: 日本病理学会総会
  • Place of Presentation: ロイトン札幌 札幌市
  • Year and Date: 2013-06-06
• [Remarks] 名古屋大学腫瘍病理学分野
  • URL: http://www.med.nagoya-u.ac.jp/patho2/
• [Patent(Industrial Property Rights)] ノックアウトマウス、内側側頭葉てんかんを抑制する物質のスクリーニング方法、及び内側側頭葉てんかんを抑制する手法の選択方法 (2015)
  • Inventor(s): 浅井真人、髙橋雅英、浅井直也、榎本篤、内山孝蔵
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-10-13
  • Overseas
• [Patent(Industrial Property Rights)] ノックアウトマウス、内側側頭葉てんかんを抑制する物質のスクリーニング方法、及び内側側頭葉てんかんを抑制する手法の選択方法 (2014)
  • Inventor(s): 浅井真人、髙橋雅英、浅井直也、榎本篤、内山孝蔵
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-10-14
  • Acquisition Date: 2015-06-26
• [Patent(Industrial Property Rights)] ノックアウトマウス、内側側頭葉てんかんを抑制する物質のスクリーニング方法、及び内側側頭葉てんかんを抑制する手法の選択方法 (2014)
  • Inventor(s): 浅井真人、高橋雅英、浅井直也、榎本篤、内山孝蔵
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-10-14