2018 Fiscal Year Final Research Report
Congenital pituitary hypoplasia modeling using induced pluripotent cells
| Project/Area Number |
16H05332
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | Kobe University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
長谷川 奉延 慶應義塾大学, 医学部(信濃町), 教授 (20189533)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | 疾患iPS細胞 / 下垂体 / 先天性下垂体形成不全 |
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| Outline of Final Research Achievements |
Anterior pituitary develops from oral ectoderm in contact with adjacent neural ectoderm that differentiates into hypothalamus with a close interaction. Here, we demonstrate iPSC-based disease modeling for congenital pituitary hypoplasia and investigated its underlying mechanisms. Using exome analysis in a patient with combined pituitary hormone deficiency, we identified a novel OTX2 mutation, of which gene product showed impaired nuclear translocation. The differentiation into pituitary in the patient-derived iPSCs (OTX2mut-iPSCs) was severely impaired. As the underlying mechanisms, the expression of an essential transcription factor for pituitary development, was diminished in OTX2mut-iPSCs. Interestingly, addition of the growth factor to the media restored the expression of transcription factor, indicating that OTX2-dependent expression of growth factor in the hypothalamus plays an important role in the pituitary differentiation.
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| Free Research Field |
内分泌学
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| Academic Significance and Societal Importance of the Research Achievements |
先天性下垂体形成不全は小児下垂体機能低下症の中で比較的頻度が高く重症化しうる疾患であるが、その原因、病態は十分に明らかになっていない。本研究では、エクソーム解析による網羅的な解析に加えて疾患特異的iPS細胞を用いたin vitroモデルによる病態解析によりその原因を明らかにすることを目的として行なった。今回疾患iPS細胞が下垂体疾患に応用可能であることを世界で初めて示しただけではなく、これまでのノックアウトマウスでは明らかにしえなかった詳細な機序の解明に繋がるとともに、表現型をレスキューする方法を見出したことから、最終的には治療応用も期待される。
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