The mechanism of actin metabolism abnormality in a hereditary small vessel disease and development of novel treatment

• Project/Area Number: 16K18387
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Yamamoto Yumi 国立研究開発法人国立循環器病研究センター, 研究所, 流動研究員 (10614927)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: CADASIL / 脳血管障害 / 脳梗塞 / 壁細胞 / 脳小血管病 / 認知症 / Notch3 / 遺伝性脳小血管病 / 病態メカニズム / 血管性認知症 / 血管平滑筋 / アクチン

Outline of Final Research Achievements

We have established a technique to differentiate iPS cells into mural cells (iPSMCs). We differentiated iPS cells from patients with hereditary small vessel disease, CADASIL into iPSMCs and compared their properties with controls. The CADASIL iPSMCs showed increased expression of PDGFRbeta and promoted migration, which were suggested to be closely involved in CADASIL pathogenesis. The knockdown of mutant NOTCH3 and/or PDGFRbeta significantly suppressed the promoted migration in CADASIL iPSMCs. These genes may be ideal targets for novel treatment of CADASIL.

Research Products

• [Journal Article] Disruption of transforming growth factor-beta superfamily signaling: A shared mechanism underlying hereditary cerebral small vessel disease (2017)
  • Author(s): Yamamoto Y and Ihara M
  • Journal Title: Neurochem Int Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Emerging evidence for pathogenesis of sporadic cerebral small vessel disease (2016)
  • Author(s): Ihara M, Yamamoto Y
  • Journal Title: Stroke Volume: 47 Issue: 2 Pages: 554-560
  • DOI: 10.1161/strokeaha.115.009627
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] In vitro model of CADASIL: iPS cell-derived mural cells for unraveling the pathogenesis of a hereditary small vessel disease. (2017)
  • Author(s): 6.Yumi Yamamoto, Katsutoshi Kojima, Daisuke Taura, Masakatsu Sone, Kazuo Washida, Naohiro Egawa, Takayuki Kondo, Eiko N Minakawa, Kayoko Tsukita, Takako Enami, Hidekazu Tomimoto, Toshiki Mizuno, Ryosuke Takahashi, Masafumi Ihara, Haruhisa Inoue.
  • Organizer: ConBio2017
  • Int'l Joint Research / Invited
• [Presentation] An iPS cell model of CADASIL: insights into the pathogenesis of a hereditary small vessel disease (2016)
  • Author(s): Y. Yamamoto
  • Organizer: 第57回日本神経学会学術大会.
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
• [Patent(Industrial Property Rights)] 特許権 (2016)
  • Inventor(s): 山本由美、猪原匡史、井上治久、月田香代子、江浪貴子
  • Industrial Property Rights Holder: 山本由美、猪原匡史、井上治久、月田香代子、江浪貴子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-12-27