2020 Fiscal Year Final Research Report
Development of newer animal model, biomarker, and treatment of depression by regulation of BDNFgene methylation using genome editing
| Project/Area Number |
18K07575
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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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| Review Section |
Basic Section 52030:Psychiatry-related
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| Research Institution | Kibi International University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
淵上 学 広島大学, 病院(医), 講師 (40403571)
田尻 直輝 名古屋市立大学, 医薬学総合研究院(医学), 准教授 (80782119)
津田 雅之 高知大学, 教育研究部医療学系基礎医学部門, 准教授 (90406182)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | 脳由来神経栄養因子(BDNF) / うつ病 / DNA methylation / Tet1 / DNMT3a |
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| Outline of Final Research Achievements |
It is known that the decreased expression of brain-derived neurotrophic factor (BDNF) in the hippocampus is associated with the pathophysiology of depression. To verify the involvement of the decreased cytosine methylation rates (CMRs) within the promoter of exon IV of the BDNF gene in the pathophysiology of depression, we developed the method of the artificial manipulation of the CMRs of the BDNF gene. Lentiviruses expressing the Fuw-dCas9-Tet1CD and Fuw-dCas9-Dnmt3a and guide RNA were produced by transfecting HEK239T cells with standard packaging vectors. After calculating the virus titer, the constructs with higher titer were transfected into the primary mouse cell culture to examine whether CMRs were altered by dCas9-Tet1 or dCas9-Dnmt3a. We found that while the dCas9-Tet1 fusion protein increased the levels of BDNF mRNA and BDNF protein with the decrease in the CMRs, the dCas9-Dnmt3a fusion protein decreased the levels of BDNF mRNA and BDNF protein with the increase in the CMRs.
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| Free Research Field |
分子精神医学
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| Academic Significance and Societal Importance of the Research Achievements |
うつ病動物モデルの脳およびうつ病患者の末梢血・脳由来DNAを対象としたBDNF遺伝子のシトシンのメチル化研究から、BDNF遺伝子exon IVのpromoter領域のメチル化率の低下が報告されている。しかしながらこれらのメチル化率の変化が、うつ病の原因として特異的な変化であるかは不明である。本研究の成果によってマウスを対象にBDNF遺伝子のメチル化を特異的に変動させる技術が開発された事になり、今後本実験で得られた手法をマウス脳に適用する事によって、うつ病の病態のエピジェネティクス領域からの一層の解明が進むと思われる。
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