Neural crest disease model using iPS cells and elucidation of pathophysiology for drug discovery

• Project/Area Number: 26860823
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Keio University
• Principal Investigator: Okuno Hironobu 慶應義塾大学, 医学部(信濃町), 助教 (70445310)
• Project Period (FY): 2014-04-01 – 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: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: CHARGE症候群 / 神経堤 / CHD7 / iPS細胞 / 遊走 / 神経堤細胞 / 方向性

Outline of Final Research Achievements

CHARGE syndrome is a disease in which organs including the heart, eyes and ears may not develop properly. The cells that form the tissues affected by CHARGE syndrome develop in embryos called neural crest cells.
We created iPSCs from CHARGE syndrome patients, developed these cells into neural crest cells, and compared them with neural crest cells that were developed from healthy individuals. The neural crest cells developed from CHARGE syndrome showed multiple abnormalities. For example, they were not able to move around correctly. This is an important observation because neural crest cells must move through tissues to form the various organs affected by CHARGE syndrome.
We also observed changes in the activity of many genes other than CHD7 in the neural crest cells developed from CHARGE patients. Further research is now needed to find out which genes are the most important for restoring the normal activity of neural crest cells.

Research Products

• [Int'l Joint Research] Stanford University(米国)
• [Int'l Joint Research] Stanford University(米国)
• [Journal Article] CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations (2017)
  • Author(s): Okuno H, Renault Mihara F, Ohta S, Fukuda K, Kurosawa K, Akamatsu W, Sanosaka T, Kohyama J, Hayashi K, Nakajima K, Takahashi T, Wysocka J, Kosaki K, Okano H.
  • Journal Title: elife Volume: 6 Pages: 23-24
  • DOI: 10.7554/elife.21114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] CHARGE症候群患者iPS細胞由来神経堤細胞を用いた病態解析 (2017)
  • Author(s): 奥野博庸
  • Organizer: 第一回慶應ライフサイエンスシンポジウム
• [Presentation] In vitro and in vivo cell dynamics analysis of iPSC-derived neural crest cells harboring CHD7 mutations reveals defective migration of CHARGE syndrome (2017)
  • Author(s): Hironobu Okuno
  • Organizer: Society for Neuroscience (SfN) 2017
  • Int'l Joint Research
• [Presentation] Differentiation of iPS cells into cranial neural crest cells to model congenital disorder that arises from defects in cranial neural crest cell development. (2016)
  • Author(s): Hironobu Okuno, Francois Renault Mihara, Shigeki Ohta, Kenji Kurosawa, Wado Akamatsu, Kenjiro Kosaki, Takao Takahashi, Hideyuki Okano
  • Organizer: The 13 th International Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Differentiation of iPS cells into cranial neural crest cells to model congenital disorder that arises from defects in the development of the embryonic cranial neural crest cell lineage. (2016)
  • Author(s): 奥野 博庸
  • Organizer: The 13th International Congress of human Genetics
  • Place of Presentation: 国立京都国際会館（京都府京都市左京区）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Modeling for abnormal neural crest cells migration in CHARGE syndrome using patient-iPSCs derived neural crest cells (2015)
  • Author(s): 奥野博庸
  • Organizer: The 55th Annual Meeting of the Japanese Teratology Society, The 38th Annual Meeting of the Japan Society of Pediatric Genetics
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市中央区)
  • Year and Date: 2015-07-28
  • Int'l Joint Research