Study for pathophysiological analysis of Hirschsprung's Disease using iPSC derived mini-gut
| Project/Area Number |
19K18167
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 55020:Digestive surgery-related
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| Research Institution | National Center for Child Health and Development |
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Principal Investigator |
Uchida Hajime 国立研究開発法人国立成育医療研究センター, 小児外科系専門診療部, 医師 (30648697)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
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| Keywords | ヒルシュスプルング病 / オルガノイド / iPS細胞 / ヒルシュスプルング病類縁 / 移植外科学 / 腸管オルガノイド |
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| Outline of Research at the Start |
腸管発生とともにヒト腸管神経叢の成り立ちを再現できる系を構築し腸管神経細胞の発生および機能不全を明らかにしていく。ヒルシュスプルング病類縁疾患（H類縁）を例にとり、疾患iPS細胞を作製しH類縁-ミニ腸疾患モデルを構築する。申請者は、試験管内で腸管神経細胞を有し蠕動様運動、吸収や分泌能などのヒト腸管の機能を有する腸管オルガノイド（ミニ腸）の創生に世界で初めて成功した。この培養システムを活用し腸管神経叢の生成と機能不全を明らかにしていく。腸管神経細胞の機能不全疾患に対し、患者自身の腸管内に内在する細胞を賦活かし腸管神経細胞の再生による新たな治療法の確立を目指す。
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| Outline of Final Research Achievements |
Our aim is to construct a system that can recapitulate human intestinal plexus as well as intestinal development, and elucidate the development and dysfunction of intestinal ganglions. Our group succeeded for the first time in the world in creating intestinal organoids (mini-guts), and have human intestinal functions such as peristalsis, absorption, and secretory capacity. In order to evaluate the slow peristalsis as much as possible, we found that the video evaluation by adding histamine is applicable as a method to select mini-intestines capable of peristalsis (mini-intestine-histamine challenge test). In the process of induction of mini-intestine differentiation, PAX3, ZIC1 and SOX10 early markers of crest cells were already expressed on day 7 from the start of differentiation induction, and their expression was observed until day 14 in the mini-gut development. We will develop the creation of loss-of-function models by genome editing of disease-related genes such as the RET gene.
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| Academic Significance and Societal Importance of the Research Achievements |
消化管の希少疾患バイオモデルの構築から初期発生、消化管神経分化を模倣する分子プログラム追跡が可能となった。小児希少疾患の疾患機序解明とともに、創薬開発では革新的なin vitro試験系開発を促進させる。今後は、ミニ腸モデルでの検証でヒトin vitro臨床試験モデルの構築を目指す。
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Report
(5 results)
Research Products
(10 results)
