神経発生に関与するシグナルの制御を標的にしたＳＭＡ病態の解明および治療薬の開発

• Project/Area Number: 17J10192
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Biological pharmacy
• Research Institution: Gifu Pharmaceutical University
• Principal Investigator: 大内 一輝 岐阜薬科大学, 薬学研究科, 特別研究員(DC2)
• Project Period (FY): 2017-04-26 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥1,900,000 (Direct Cost: ¥1,900,000); Fiscal Year 2018: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2017: ¥1,000,000 (Direct Cost: ¥1,000,000)
• Keywords: ＳＭＡ / アストロサイト / Notchシグナル / 治療薬の開発 / SMA

Outline of Annual Research Achievements

前年度は、アストロサイトの脊髄性筋萎縮症 (SMA) への関与をSMAモデルマウス及び患者iPS細胞を用いたin vitro SMA モデルを使用して検討した。その結果、SMA病態下でNotchシグナルの活性化を介して、アストロサイトの分化及び増殖が亢進している可能性が示唆された。
そこで当該年度は、アストロサイトの分化及び増殖を制御するNotchシグナルを阻害した際に、SMAモデルマウスの生存期間及び運動機能にどのような影響が出るかを検討した。その結果、Notchシグナル阻害薬はSMAモデルマウスの生存期間 (未処置群でおよそ2週間程度) に影響を及ぼさなかったが、正向反射ならびに傾斜板法による運動機能低下の進行を抑制した。さらにNotchシグナル阻害薬はSMA病態下のアストロサイトの増殖を抑制した。これらの結果には当初予定していなかった内容も含んでいるが、一年を通して期待通りの研究の進展が認められた。これらの研究成果は、SMAにおけるアストロサイト病変のメカニズムの一端を明らかにするものであり、Notchシグナルを標的にした、SMAの新たな治療戦略を提供できるものと考える。つまり、現状のSMA患者及びその他神経変性疾患患者のQOL向上に貢献できる治療薬の開発につながると考えられる。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Notch Signaling Mediates Astrocyte Abnormality in Spinal Muscular Atrophy Model Systems (2019)
  • Author(s): Ohuchi Kazuki、Funato Michinori、Yoshino Yuta、Ando Shiori、Inagaki Satoshi、Sato Arisu、Kawase Chizuru、Seki Junko、Saito Toshio、Nishio Hisahide、Nakamura Shinsuke、Shimazawa Masamitsu、Kaneko Hideo、Hara Hideaki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 3710-3710
  • DOI: 10.1038/s41598-019-39788-w
  • Peer Reviewed / Open Access
• [Journal Article] Impairment of oligodendrocyte lineages in Spinal Muscular Atrophy Model Systems (2019)
  • Author(s): Ohuchi K, Funato M, Ando S, Inagaki S, Sato A, Kawase C, Seki J, Nakamura S, Shimazawa M, Kaneko H and Hara H
  • Journal Title: NeuroReport Volume: 30(5) Issue: 5 Pages: 350-357
  • DOI: 10.1097/wnr.0000000000001206
  • Peer Reviewed / Open Access
• [Journal Article] Impaired cerebellar development in mice overexpressing VGF (2019)
  • Author(s): Mizoguchi T, Shimazawa M Ohuchi K, Kuse Y, Nakamura S and Hara H.
  • Journal Title: Neurochemical Research, Volume: 44(2) Issue: 2 Pages: 374-387
  • DOI: 10.1007/s11064-018-2684-7
  • Peer Reviewed
• [Journal Article] A docosahexaenoic acid-derived pro-resolving agent, maresin 1, protects motor neuron cells death (2018)
  • Author(s): Ohuchi K., Ono Y., Joho M., Tsuruma K., Ogami S., Yamane S., Funato M., Kaneko H., Nakamura S., Hara H. and Shimazawa M
  • Journal Title: Neurochemical Research Volume: 43(7) Issue: 7 Pages: 1413-1423
  • DOI: 10.1007/s11064-018-2556-1
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of Prednisolone in Generated Myotubes Derived from Fibroblasts of Duchenne Muscular Dystrophy Patients (2018)
  • Author(s): Kameyama T., Ohuchi K., Funato M., Ando S., Inagaki S., Sato A., Seki J., Kawase C., Tsuruma K., Nishino I., Nakamura S., Shimazawa M., Saito T., Takeda S., Kaneko H. and Hara H
  • Journal Title: Frontiers in pharmacology Volume: 9:1402 Pages: 1-12
  • DOI: 10.3389/fphar.2018.01402
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Timolol on Optineurin Aggregation in Transformed Induced Pluripotent Stem Cells Derived From Patient With Familial Glaucoma. (2018)
  • Author(s): Inagaki S, Kawase K, Funato M, Seki J, Kawase C, Ohuchi K, Kameyama T, Ando S, Sato A, Morozumi W, Nakamura S, Shimazawa M, Iejima D, Iwata T, Yamamoto T, Kaneko H, Hara H.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 59(6) Issue: 6 Pages: 2293-2304
  • DOI: 10.1167/iovs.17-22975
  • Peer Reviewed / Open Access
• [Journal Article] Microglia increases the proliferation of retinal precursor cells during postnatal development (2018)
  • Author(s): Kuse Y., Ohuchi K., Nakamura S., Hara H. and Shimazawa M.
  • Journal Title: Molecular Vision Volume: 24 Pages: 536-545
  • Peer Reviewed / Open Access
• [Journal Article] GPNMB ameliorates mutant TDP-43-induced motor neuron cell death. (2017)
  • Author(s): Nagahara Y, Shimazawa M, Ohuchi K, Ito J, Takahashi H, Tsuruma K, Kakita A, Hara H
  • Journal Title: J Neurosci Res Volume: 95 Issue: 8 Pages: 1647-1665
  • DOI: 10.1002/jnr.23999
  • Peer Reviewed
• [Journal Article] Edaravone is a candidate agent for spinal muscular atrophy: In vitro analysis using a human induced pluripotent stem cells-derived disease model. (2017)
  • Author(s): Ando S, Funato M, Ohuchi K, Kameyama T, Inagaki S, Seki J, Kawase C, Tsuruma K, Shimazawa M, Kaneko H, Hara H.
  • Journal Title: Eur J Pharmacol. Volume: 814 Pages: 161-168
  • DOI: 10.1016/j.ejphar.2017.08.005
  • Peer Reviewed / Open Access
• [Presentation] 脊髄性筋萎縮症病態におけるNG2グリアの関与 (2019)
  • Author(s): 大内一輝、舩戸 道徳、川瀬 千鶴、関 順子、安藤 栞、稲垣 賢、中村 信介、嶋澤 雅光、金子 英雄、原 英彰
  • Organizer: 第18回日本再生医療学会
• [Presentation] VGF過剰発現マウスにおける小脳神経細胞の発生異常 (2018)
  • Author(s): 溝口貴洋、嶋澤雅光、大内一輝、久世祥己、中村信介、原英彰
  • Organizer: 第27回海馬と高次脳機能学会
• [Presentation] The oligodendrocyte derived from familial glaucoma patients-iPSCs decreases neuroprotective action for retinal ganglion cells. (2018)
  • Author(s): Inagaki S, Kawase K, Funato M, Ohuchi K, Ando S, Sato A, Morozumi W, Shimazawa M, Iejima D, Iwata T, Yamamoto T, Kaneko H, Hara H.
  • Organizer: ARVO 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] Impaired cerebellar development in mice overexpressing VGF nerve growth factor inducible (VGF) via promoting MAPK signaling (2018)
  • Author(s): Mizoguchi T, Shimazawa M, Ohuchi K, Nakamura S, Hara H.
  • Organizer: 31th CINP World Congress of Neuropsychopharmacology
  • Int'l Joint Research
• [Presentation] The inhibition of Notch signaling ameliorates the motor functional deficits and astrocytic abnormality of in vitro and in vivo spinal muscular atrophy models. (2018)
  • Author(s): Ohuchi K, Funato M, Yoshino Y, Ando S, Inagaki S, Kawase C, Seki J, Nakamura S, Shimazawa M, Kaneko H, Hara H.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] The protective effects of levetiracetam on spinal muscular atrophy models. (2018)
  • Author(s): Ando S, Ohuchi K, Funato M, Nakamura S, Shimazawa M, Kaneko H, Hara H.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] A docosahexaenoic acid-derived pro-resolving agent, maresin 1, protects neurodegeneration in vitro and in vivo. (2018)
  • Author(s): Ohuchi K, Ono Y, Joho M, Ogami S, Yamane S, Funato M, Kaneko H, Nakamura S, Shimazawa M, Hara H.
  • Organizer: The 2nd International Conference & Expo on Pharmacology & Regulatory Affairs
  • Int'l Joint Research
• [Presentation] Establishment of in vitro Bloom syndrome model using BS-iPSC (2018)
  • Author(s): Kazuki Ohuchia,b, Chizuru Kawaseb, Michinori Funatob, Junko Sekib, Yasuhiro Ikawac, Akihiro Yachiec, Hideaki Haraa and Hideo Kaneko
  • Organizer: International Meeting on RECQ Helicases and Related Diseases 2018
  • Int'l Joint Research
• [Presentation] The Protective Effects of Edaravone in Generated Spinal Motor Neuron Using iPSCs Derived from a Spinal Muscular Atrophy Patient (2017)
  • Author(s): Ando S., Funato M., Ohuchi K., Tsuruma K., Shimazawa M., Kaneko H. and Hara H.
  • Organizer: 14th Asian and Oceanian Congress of Child Neurology
  • Int'l Joint Research
• [Presentation] 小脳の発達期組織形成におけるVGFの役割 (2017)
  • Author(s): 溝口貴洋、大内一輝、嶋澤雅光、原英彰
  • Organizer: 生体機能と創薬シンポジウム2017
• [Presentation] マウス網膜発生期におけるミクログリアの関与 (2017)
  • Author(s): 久世祥己、大内一輝、中村信介、嶋澤雅光、原英彰
  • Organizer: 第132回日本薬理学会近畿部会
• [Patent(Industrial Property Rights)] 脊髄性筋萎縮症治療薬 (2018)
  • Inventor(s): 原 英彰、大内一輝、舩戸道徳、金子英雄
  • Industrial Property Rights Holder: 原 英彰、大内一輝、舩戸道徳、金子英雄
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-055331
  • Filing Date: 2018