2018 Fiscal Year Final Research Report
Construction of evaluation system for vitamin D analogs using genetically modified rats with genome editing
| Project/Area Number |
16H04912
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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 |
Applied biochemistry
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| Research Institution | Toyama Prefectural University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
橘高 敦史 帝京大学, 薬学部, 教授 (00214833)
中川 公恵 神戸薬科大学, 薬学部, 准教授 (90309435)
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| Research Collaborator |
IKUSHIRO SHINICHI
YAUSDA KAORI
NISHIKAWA MIYU
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | ビタミンD / ゲノム編集 / ビタミンD受容体 / シトクロムP450 / 遺伝子改変 / ビタミンD代謝酵素 / 作用メカニズム / 疾患モデル動物 |
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| Outline of Final Research Achievements |
The gene-deficient rats of CYP27B1, CYP24A1, or vitamin D receptor were successfully produced by the genome-editing method using the CRISPR/Cas9 system. In addition, the type II rickets model rats with the mutant VDR (R270L) whose affinity for 1α,25-dihydroxyvitamin D3 (1,25D3) was reduced to the same extent as 25-hydroxyvitamin D3 (25D3) were produced. Comparison of physiological properties among the wild-type and these genetically modified rats and comparison of the effects of 25-hydroxyvitamin D3 administration provided much knowledge on the role of 1,25D3 and 25D3 in osteogenesis, skin and hair follicle formation, and homeostasis of blood Ca levels. Furthermore, the novel metabolic pathways of 1,25D3 and 25D3 by CYP24A1 and CYP3A1/2 were revealed.
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| Free Research Field |
遺伝子工学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究ではビタミンD受容体に低い親和性を示すリガンドが多量に存在すれば、親和性が高いリガンドが存在しなくてもビタミンD作用を補完できることを示した。これは生理的に意味があるビタミンDは親和性がきわめて高い1,25D3であるというこれまでの常識を覆した結果であり、学術的価値が高い。また、25D3がI型くる病（CYP27B1遺伝子欠損）だけでなく腎機能が低下した患者にも有効であり、II型くる病（VDR変異）にも高い治療効果を有することを示唆した。さらに、ビタミンD誘導体AH-1がII型くる病（VDR変異）に対し高い治療効果を示し、医薬品として有望であることを明らかにしたため、社会的意義が大きい。
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