Development of fundamental therapy for dopamine-related disorders targetting novel protein complex V-1/CP
| Project/Area Number |
16K08904
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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 |
Applied pharmacology
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Research Collaborator |
Yamakuni Tohru , 准教授
Kobayashi Kazuto , 教授
Ichinose Hiroshi , 教授
Hasegawa Kazuko , 医師
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
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)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | V-1/CP complex / tyrosine hydroxylase / Nurr1 / dopamine / aging / Parkinson's disease / nicotine receptor / NMDA receptor / V-1/CP複合体 / 老化 / パーキンソン病 / アルツハイマー病 / ドパミン / チロシン水酸化酵素 / 血清応答因子 / アクチン重合 / カテコールアミン / 加齢 / ドーパ脱炭酸酵素 / NMDA受容体 / ドーパミン |
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| Outline of Final Research Achievements |
V-1/CP complex formation is essential to maintain dopaminergic function, and the complex promotes dopamine biosynthesis by some stimulation (KAKENHI23790594, 25860389). In this study, we approached the mechanism to activate V-1/CP complex and screened novel compounds targetting V-1/CP that facilitate the complex formation then verified their therapeutic effects. We revealed that the complex is activated by NMDA receptors and nicotinic acetylcholine receptors to potentiate dopaminergic function and neuroprotective abilities to enhance cell survival. Furthermore, we found the complex formation of V-1/CP was attenuated by aging and in the postmortem brain of human with Parkinson's disease (PD). We also successfully identified natural compounds targetting V-1/CP complex and revealed the compounds could activate the complex to recover dopaminergic function and cell survival in aged or PD model. Thus, the therapeutics targetting V-1/CP complex is useful for PD and anti-aging treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
日本では超高齢化が進み、高齢者で多発するパーキンソン病患者の数が増加している。パーキンソン病の対症療法薬はあるものの、これまで根本治療薬は開発されていない。私たちはV-1/CPという新しいタンパク質複合体に着目し、そのドパミン機能の強力な賦活化作用を明らかにしてきた。本研究では同複合体がNMDA受容体やニコチン受容体により活性化される新しい機序を明らかにし、同複合体を標的とした新たな化合物のスクリーニングに成功した。またパーキンソン病や加齢によって同複合体が減少し、新規化合物により回復可能であることを明らかにした。これらの成果から、同複合体を標的としたドパミン疾患治療薬の開発が期待できる。
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Report
(4 results)
Research Products
(13 results)
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[Presentation] V-1/CP complex formation is required for genetic co-regulation of adult nigrostriatal dopaminergic homeostatis via the RHO/MAL/SRF pathway in vitro and in vivo2018
Author(s)
Ichiro Kawahata, Yensin Lai, Junichi Morita, Shigeki Kato, Shiori Ohtaku, Yoshihisa Tomioka, Akiko Tabuchi, Masaaki Tsuda, Chiho Ichinose, Katsunori Kondo, Yasuhiko Izumi, Toshiaki Kume, Akinori Akaike, Kazumasa Ohashi, Kensaku Mizuno, Kazuko Hasegawa, Hiroshi Ichinose, Kazuto Kobayashi, Tohru Yamakuni
Organizer
Neuroscience 2018
Related Report
Int'l Joint Research
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[Presentation] V-1/CP complex formation is required for genetic co-regulation of adult nigrostriatal dopaminergic function via the RHO/MAL/SRF pathway in vitro and in vivo2017
Author(s)
Ichiro Kawahata, Yensin Lai, Junichi Morita, Shigeki Kato, Shiori Ohtaku, Yoshihisa Tomioka, Akiko Tabuchi, Masaaki Tsuda, Chiho Ichinose, Katsunori Kondo, Yasuhiko Izumi, Toshiaki Kume, Akinori Akaike, Kazumasa Ohashi, Kensaku Mizuno, Kazuko Hasegawa, Hiroshi Ichinose, Kazuto Kobayashi, Tohru Yamakuni
Organizer
XXIII World Congress of Neurology
Related Report
Int'l Joint Research
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