2021 Fiscal Year Final Research Report
Elucidation of the pathogenic mechanisms of microglial dysfunction and neurodevelopmental disorder
| Project/Area Number |
19K16918
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 51030:Pathophysiologic neuroscience-related
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | レット症候群 / MeCP2 / ミクログリア / TLR9 |
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| Outline of Final Research Achievements |
We crossed MeCP2-KO mice and Toll-like receptor 9 (TLR9), which is highly expressed in the microglia of immune-competent cells in the brain and recognizes DNA derived from bacteria and viruses, -KO mice. We found that TLR9/MeCP2 double-KO mice had a significantly longer life span than MeCP2-KO mice. We also found that microglial activation was suppressed in TLR9/MeCP2 double-KO mice compared to MeCP2-KO mice. Treatment of MeCP2-deficient mice with X, an inhibitor of the putative ligand for TLR9, improved the RTT-like phenotype observed in MeCP2-KO mice and extended their life span.
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| Free Research Field |
神経科学
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| Academic Significance and Societal Importance of the Research Achievements |
MeCP2遺伝子変異は、Rett症候群(RTT)をはじめ、自閉症、統合失調症などを含めた様々な精神疾患・発達障害への関与が示唆されているが、発症機序の詳細は不明である。本研究では、MeCP2KOマウスで観察されるミクログリアの活性化がRTT病態発症に関与しているとの仮説のもと、TLR9シグナルを抑制することでRTT様の表現型が改善することを見出した。今後は、TLR9のリガンドを同定しそのシグナル阻害剤などを投与することでRTT様の表現型が改善するかどうかを解析し、治療薬の開発へと繋げていきたい。
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