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2022 Fiscal Year Final Research Report

Study on development of novel antipsychotics based on reverse translational research

Research Project

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Project/Area Number 20K07082
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47040:Pharmacology-related
Research InstitutionFujita Health University

Principal Investigator

Nagai Taku  藤田医科大学, その他部局等, 教授 (10377426)

Project Period (FY) 2020-04-01 – 2023-03-31
Keywords統合失調症 / 遺伝子変異 / マウス
Outline of Final Research Achievements

We recently found a significant association between exonic copy-number variations in the Rho GTPase activating protein 10 (Arhgap10) gene and schizophrenia in Japanese patients. Accordingly, we generated a mouse model (Arhgap10 mutant mice) carrying a missense variant and a coexisting frameshift mutation. The expression levels of phosphorylated MYPT-1 and PAK1/2 in the striatum and nucleus accumbens (NAc) were increased in Arhgap10 mutant mice compared with wild-type littermates. Arhgap10 mutant mice exhibited an increase in neuronal complexity and spine density in the striatum and NAc. The number of c-Fos-positive cells was significantly increased after methamphetamine treatment in the dorsomedial striatum and NAc core of Arhgap10 mutant mice. These results suggested that schizophrenia-associated Arhgap10 gene mutations result in morphological abnormality of neurons in the striatum and NAc.

Free Research Field

神経薬理学

Academic Significance and Societal Importance of the Research Achievements

統合失調症は、重大な精神疾患であり、現在の治療では十分な効果が得られない難治例も多い。現在、精神疾患の診断は精神症候学に依拠しており、病態を反映した客観的な診断法はなく、治療法の開発も遅れている。統合失調症の発症に関する遺伝的寄与は大きいと推測されているが、発症メカニズムの詳細は未だ不明であり、病態に基づく治療薬開発が進んでいないのが現状である。本研究課題では、神経化学、形態学および行動薬理学を融合させた包括的解析を実施することにより統合失調症患者で同定されたARHGAP10遺伝子変異の病態生理学的意義を明らかにすることができた。Rhoシグナルを標的とした新規治療薬の開発に繋がる成果を示した。

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Published: 2024-01-30  

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