2018 Fiscal Year Final Research Report
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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| Keywords | V-1/CP complex / tyrosine hydroxylase / Nurr1 / dopamine / aging / Parkinson's disease / nicotine receptor / NMDA receptor |
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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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| Free Research Field |
神経科学、神経薬理学
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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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