Elucidation of the mechanism of Sortilin reduction by prion infection and its application to therapeutic method development
| Project/Area Number |
17K08859
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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 |
Virology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
UCHIYAMA Keiji 徳島大学, 先端酵素学研究所(次世代), 准教授 (60294039)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 異常プリオン / ソーティリン / エタノールアミン / T0901317 / Liver X receptor / 抗プリオン活性 / プリオン病 / プリオン |
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| Outline of Final Research Achievements |
In this study, it was suggested that one of the mechanisms that reduces the expression of Sortilin by prion infection is that the interaction between Sortilin and the retromer complex is restricted, which suppresses the retrieval of Sortilin from endosomes into the trans-Golgi network and causes excessive influx into lysosomes. Consequently, it was thought that the expression level of sortilin was decreased by prion infection.
In addition, it was found that ethanolamine and Liver X receptor agonist (T0901317) upregulated CH25H expression, which converts cholesterol to 25-hydroxycholesterol. It was also shown that the 25-hydroxycholesterol has an anti-prion activity and decreases abnormal prion protein, and recovers Sortilin expression level. Furthermore, it was shown that these compounds prolong the survival time of prion infected mice in prion infection experiments.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、プリオン感染によるソーティリン発現量低下を回復し、さらに、異常プリオンの減少を引き起こす新規抗プリオン活性物質として、エタノールアミンおよびLiver X receptor（LXR）のアゴニストであるT0901317を同定した。これらはともに、25HCを介して抗プリオン活性を示していると考えられ、今後、25HCの抗プリオン活性発現機構を明らかにすることで、プリオン病に対する新たな治療方策や治療標的が同定されると考えられる。また、LXR活性化が抗プリオン活性を示すことから、LXRをターゲットとした新たな創薬の可能性が示された。
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Report
(2 results)
Research Products
(8 results)
