疾患iPS細胞を用いた脳タンパク質老化モデルの構築と治療薬の開発

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 17H05706
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Juntendo University
• Principal Investigator: 赤松 和土 順天堂大学, 医学(系)研究科(研究院), 特任教授 (60338184)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: iPS細胞 / 神経細胞 / 老化 / 神経幹細胞 / 神経変性疾患 / パーキンソン病 / αシヌクレイン / 神経科学 / 神経変性

Outline of Annual Research Achievements

実際の患者で数十年を要する神経変性疾患の細胞老化を疾患iPS細胞由来ニューロンの短期間の培養で再現する手法として、早老症の原因タンパク質であるプロジェリンの導入やテロメア合成酵素の阻害を用いた方法が報告されているが、手技が煩雑かつ細胞への効果が均一でなく、さらにニューロンではその効果が弱いことが示されている。低分子化合物を添加することで細胞老化を促進することができれば、より簡便に晩期発症の神経変性疾患の病態を再現することが可能になると考えた。我々は化合物スクリーニングにより神経成熟を促進する低分子化合物を数種類同定し、そのうちの1種類の化合物が神経前駆細胞からニューロンへの分化効率を上昇させることを発見した。さらにこの低分子化合物の添加でiPS細胞由来ニューロンだけでなく培養細胞一般の細胞老化が促進することを多面的な表現型で確認することができた。さらに従来の方法で病態の再現が難しかった晩期発症の神経変性疾患の表現型発現までの時間を大きく短縮することを確認した。

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] Induced Pluripotent Stem Cells Reprogrammed with Three Inhibitors Show Accelerated Differentiation Potentials with High Levels of 2-Cell Stage Marker Expression (2019)
  • Author(s): Nishihara Koji、Shiga Takahiro、Nakamura Eri、Akiyama Tomohiko、Sasaki Takashi、Suzuki Sadafumi、Ko Minoru S.H.、Tada Norihiro、Okano Hideyuki、Akamatsu Wado
  • Journal Title: Stem Cell Reports Volume: 12 Issue: 2 Pages: 305-318
  • DOI: 10.1016/j.stemcr.2018.12.018
  • Peer Reviewed / Open Access
• [Journal Article] Zonisamide Administration Improves Fatty Acid β-Oxidation in Parkinson's Disease. (2018)
  • Author(s): Ueno SI, Saiki S, Fujimaki M, Takeshige-Amano H, Hatano T, Oyama G, Ishikawa KI, Yamguchi A, Nojiri S, Akamatsu W, Hattori N.
  • Journal Title: Cells Volume: 8 Issue: 1 Pages: 14-14
  • DOI: 10.3390/cells8010014
  • Peer Reviewed / Open Access
• [Journal Article] Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease (2018)
  • Author(s): Ren Qian、Ma Min、Yang Jun、Nonaka Risa、Yamaguchi Akihiro、Ishikawa Kei-ichi、Kobayashi Kenta、Murayama Shigeo、Hwang Sung Hee、Saiki Shinji、Akamatsu Wado、Hattori Nobutaka、Hammock Bruce D.、Hashimoto Kenji
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 25
  • DOI: 10.1073/pnas.1802179115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rostrocaudal Areal Patterning of Human PSC-Derived Cortical Neurons by FGF8 Signaling (2018)
  • Author(s): Imaizumi Kent、Fujimori Koki、Ishii Seiji、Otomo Asako、Hosoi Yasushi、Miyajima Hiroaki、Warita Hitoshi、Aoki Masashi、Hadano Shinji、Akamatsu Wado、Okano Hideyuki
  • Journal Title: eNeuro Volume: 5 Issue: 2 Pages: 0368-17
  • DOI: 10.1523/eneuro.0368-17.2018
  • Peer Reviewed / Open Access
• [Journal Article] Down-regulation of ghrelin receptors on dopaminergic neurons in the substantia nigra contributes to Parkinson's disease-like motor dysfunction. (2018)
  • Author(s): Suda Y, Kuzumaki N, Sone T, Narita M, Tanaka K, Hamada Y, Iwasawa C, Shibasaki M, Maekawa A, Matsuo M, Akamatsu W, Hattori N, Okano H, Narita M.
  • Journal Title: Mol Brain. Volume: 11 Issue: 1 Pages: 6-6
  • DOI: 10.1186/s13041-018-0349-8
  • Peer Reviewed / Open Access
• [Journal Article] Chemical decontamination of iPS cell-derived neural cell mixtures (2018)
  • Author(s): Mao Di、Chung Xie Khim Watson、Andoh-Noda Tomoko、Qin Ying、Sato Shin-ichi、Takemoto Yasushi、Akamatsu Wado、Okano Hideyuki、Uesugi Motonari
  • Journal Title: Chem Commun (Camb). 1355 Volume: 54 Issue: 11 Pages: 1355-1358
  • DOI: 10.1039/c7cc08686e
  • Peer Reviewed
• [Journal Article] Escape from Pluripotency via Inhibition of TGF-β/BMP and Activation of Wnt Signaling Accelerates Differentiation and Aging in hPSC Progeny Cells (2017)
  • Author(s): Fujimori Koki、Matsumoto Takuya、Kisa Fumihiko、Hattori Nobutaka、Okano Hideyuki、Akamatsu Wado
  • Journal Title: Stem Cell Reports. Volume: 9 Issue: 5 Pages: 1675-1691
  • DOI: 10.1016/j.stemcr.2017.09.024
  • Peer Reviewed / Open Access
• [Journal Article] Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson’s disease (2017)
  • Author(s): Shiba-Fukushima Kahori、Ishikawa Kei-Ichi、Inoshita Tsuyoshi、Izawa Nana、Takanashi Masashi、Sato Shigeto、Onodera Osamu、Akamatsu Wado、Okano Hideyuki、Imai Yuzuru、Hattori Nobutaka
  • Journal Title: Human Molecular Genetics Volume: 26 Pages: 3172-3185
  • DOI: 10.1093/hmg/ddx201
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of neural cells using iPSCs from sleep bruxism patients with 5-HT2A polymorphism (2017)
  • Author(s): Hoashi Y, Okamoto S, Abe Y, Matsumoto T, Tanaka J, Yoshida Y, Imaizumi K, Mishima K, Akamatsu W, Okano H, Baba K
  • Journal Title: Journal of Prosthodontic Research Volume: 61 Issue: 3 Pages: 242-250
  • DOI: 10.1016/j.jpor.2016.11.003
  • NAID: 130006076280
  • ISSN: 1883-1958, 1883-9207
  • Peer Reviewed
• [Journal Article] Assessment of Mitophagy in iPS Cell-Derived Neurons. (2017)
  • Author(s): Ishikawa KI, Yamaguchi A, Okano H, Akamatsu W.
  • Journal Title: Methods Mol Biol. Volume: - Pages: 1-9
  • DOI: 10.1007/7651_2017_10
  • ISBN: 9781493977499, 9781493977505
  • Peer Reviewed
• [Journal Article] Changeability of the fully methylated status of the 15q11.2 region in induced pluripotent stem cells derived from a patient with Prader-Willi syndrome. (2016)
  • Author(s): Okuno H, Nakabayashi K, Abe K, Ando T, Sanosaka T, Kohyama J, Akamatsu W, Ohyama M, Takahashi T, Kosaki K, Okano H.
  • Journal Title: Congenit Anom (Kyoto) Volume: Dec 21 Issue: 4 Pages: 96-103
  • DOI: 10.1111/cga.12206
  • NAID: 130008142312
  • Peer Reviewed
• [Presentation] Patient-specific iPS cells for neural disease modeling and drug screening (2018)
  • Author(s): 赤松和土
  • Organizer: 国際シンポジウム早老症と関連疾患 2018（RECQ2018）
  • Int'l Joint Research / Invited
• [Presentation] iPS細胞を用いた神経疾患の病態解析 (2018)
  • Author(s): 赤松和土
  • Organizer: iCell Users' Meeting 2018
  • Invited
• [Presentation] Patient-specific iPS cells for neural disease modeling and drug screening (2017)
  • Author(s): 赤松和土
  • Organizer: 65th Annual Meeting of Japanese Association for Dental Research
  • Int'l Joint Research / Invited
• [Patent(Industrial Property Rights)] 神経細胞の成熟老化促進剤 (2018)
  • Inventor(s): 赤松和土
  • Industrial Property Rights Holder: 赤松和土
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-077304
  • Filing Date: 2018