2023 Fiscal Year Final Research Report
The Role of medical olivocochlear-outer hair cell synapse in age-related hearing loss: Insights from Cbln1 knockout mice
| Project/Area Number |
20K09727
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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 56050:Otorhinolaryngology-related
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
Fujikawa Taro 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (60401402)
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Keywords | Age-related hearing loss / Cochlear synaptopathy / Outer hair cell / Cerebellin-1 |
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| Outline of Final Research Achievements |
This study elucidated localization and function of cerebellin-1 (Cbln1) in the mouse cochlea. Cbln1 expressed in synaptic clefts of the medial olivocochlear/outer hair cell (MOC/OHC) synapses, which form a negative-feedback gain-control system in the cochlea. Cbln1-deficient (Cbln1-/-) mice had immature MOC/OHC synapses and progressive high-frequency hearing loss. Under noise-induced transient threshold shift condition, Cbln1-/- mice showed permanent threshold shifts due to irreversible OHC dysfunction and exacerbation of cochlear synaptopathy. Remarkably, adeno-associated virus-mediated Cbln1 transduction in the cochlea resulted in attenuated threshold shifts in Cbln1-/- mice and reduced synaptopathy in wild-type mice. The findings suggest that Cbln1 is a synaptic organizer in the cochlea and the deficiency causes vulnerability to noise exposure and exacerbation of cochlear synaptopathy. Cbln1 can be a new target of gene therapy for noise-induced or age-related hearing loss.
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| Free Research Field |
Otolaryngology
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| Academic Significance and Societal Importance of the Research Achievements |
高齢化人口の増加と共に加齢性難聴が健康寿命にかかわる大きな問題となっている。加齢性難聴の病態に蝸牛シナプス病があるがその分子機構は不明な点が多い。Cerebellin-1（Cbln1）は中枢神経系の強力なシナプス形成因子であることが知られているが、本研究からCbln1が蝸牛遠心性シナプスの形成に重要であり、その不全により過剰音響刺激に対する脆弱性が増し蝸牛シナプス病を増悪させることがわかった。蝸牛シナプス病のメカニズムの一端を分子レベルで明らかにしたのは本研究が初めてである。外因性Cblnによる難聴の遺伝子治療や予防などへの応用が期待される。
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