| Project/Area Number |
16K08225
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Hokkaido University |
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Principal Investigator |
Maita Hiroshi 北海道大学, 薬学研究院, 講師 (60431318)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | スプライシング / ケミカルバイオロジー / CDK9 / pre-mRNAスプライシング / 転写スプライシング共役機構 / 低分子化合物 / RNA-seq / スプライソソーム / pre-mRNA スプライシング / snRNP |
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| Outline of Final Research Achievements |
In our previous study, we have developed a reporter gene that contains the splice site mutation. We have screened small compounds using the reporter gene to identify hit compounds that can correct the splicing pattern of the reporter gene. A compound was successfully found and then we analyzed changes of transcriptome by RNA-seq. Transcriptome analysis revealed that the compound significantly reduced the normally retained introns, which may be interpreted as a result of transcription repression because generally half-life of introns are shorter than mature mRNA. In addition, this compound has been reported to block CDK9, a kinase stimulating transcription elongation by phosphorylating RNA polymerase II. Therefore, we hypothesized that the splicing modulating activity of the compound is based on inhibition of CDK9 and further analysis confirmed that CDK9 inhibitors have indeed an activity to modulate splicing, which suggest the novel approach to modulate splicing.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では遺伝性疾患の原因遺伝子変異のうち、mRNAの編集に必要なスプライシング反応に異常を誘発する変異に着目した。スプライシング反応を異常にする変異があっても正常なスプライシングを可能にする薬があれば、このタイプの変異による遺伝性疾患は治療できる可能性がある。実際、スプライシング調節による治療法自体はすでに開発されており、RNAに張り付いてスプライシングを調節する核酸医薬が承認されている。ただし、これは遺伝子特異的な治療薬であり、広範なスプライシング異常を是正する低分子化合物は存在しない。本研究ではそのような活性化合物を探索し、作用の仕組みを明らかにすることを目的とした。
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