| 研究課題/領域番号 |
23K06303
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| 研究種目 |
基盤研究(C)
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| 配分区分 | 基金 |
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| 応募区分 | 一般 |
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| 審査区分 |
小区分48010:解剖学関連
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| 研究機関 | 大阪大学 |
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研究代表者 |
Tu HungYa 大阪大学, 蛋白質研究所, 助教 (10780835)
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| 研究期間 (年度) |
2023-04-01 – 2026-03-31
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| 研究課題ステータス |
交付 (2023年度)
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| 配分額 *注記 |
4,680千円 (直接経費: 3,600千円、間接経費: 1,080千円)
2025年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円)
2024年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円)
2023年度: 1,690千円 (直接経費: 1,300千円、間接経費: 390千円)
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| キーワード | retina / synapse / photoreceptor cell / bipolar cell / deconstruction / reconstruction / neuroplasticity / electrophysiology |
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| 研究開始時の研究の概要 |
By analyzing the mouse models of retinal synaptic impairment and recovery at different stages, this project aims to find out the regulatory mechanisms of synapse remodeling and neural circuitry reconstruction in the retina to help further augment the development of regeneration medicines.
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| 研究実績の概要 |
The purpose of this project is to elucidate 1) whether the photoreceptor and bipolar cells still possess the plasticity and potential to reorganize their synaptic connection in the mature mammalian retina, and 2) based on that how the cell replacement based therapy may be advanced. We first established the mouse models of inducible photoreceptor-bipolar synaptic deconstruction and reconstruction, both partially and completely, using the CreERT2 system. Tamoxifen-inducible conditional knockout (CKO) of Pikachurin, the one presumably resulting in partial synaptic impairment by depleting the photoreceptor-origin synaptic organizer, has been first launched and showed a limited time window right after the retinal circuitry is established, to effectively disrupt the synaptic organization followed by a delayed functional reduction, suggesting the Pikachurin proteins may be protected after implemented into the synapse and have a slow turn-over rate, or there is at least a limited period for the synapses to retain their structures even without the synaptic organizer. The mouse line for the (presumable) complete synaptic deconstruction by removing Trpm1, one of the key component on the bipolar cell side, has recently become ready, as well as the conditional rescue models of these two CKO models.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
The preparation of mouse lines took slightly longer than expected due to the need for clearance of mouse strain background issue and the limited breeding yields because of the complexity of combining multiple CreERT2 lines and fluorescence-based reporter lines. However, with the first-launched CKO line, the protocol of tamoxifen-based induction has been established, with an effective time window identified preliminarily.
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| 今後の研究の推進方策 |
By retinal immunohistochemistry and electrophysiology at both animal-level (optokinetic response) and cell-level (multielectrode array recording), the structural and functional potential of synaptic deconstruction and, more importantly, reconstruction will be evaluated in detail to provide insight for cell replacement based therapeutic advancement.
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