神经营养因子促进听神经带状突触再生和听力恢复的机制研究

Noise-induced and age-related hearing loss are the most common forms of auditory disorders in modern society. Recent findings suggest that degeneration of the ribbon synapses is an early pathological hallmark in noise-exposed and aging cochlea. This synaptic degeneration can have prolonged and cumulative effects, and could lead to eventually death of the auditory neurons. We have previously found that neurotrophin-3 (NT-3), but not the closely-related family member BDNF, promotes regeneration of the ribbon synapses and recovery of the hearing sensitivity after noise exposure. In this proposal, we will develop noise-induced and age-related hearing loss mouse models, in which synaptic degeneration occurs preferentially and precedes loss of sensory hair cells or neurons. With these mouse models, we aim to identify the downstream targets and molecular mechanisms of NT-3 in promoting maintenance and regeneration of ribbon synapses. We will also investigate if NT-3 and its candidate targets could also restore synaptic connections in the aging cochlea. Findings from this proposal will not only provide novel therapeutic targets for sensorineural hearing loss, but also reveal the molecular mechanisms underlying synaptic remodeling and regeneration in general.

噪声性和老年性耳聋是现代社会最常见的听力功能障碍。最新的研究表明在噪声暴露或老龄化的耳蜗中，内毛细胞和听神经之间的带状突触最先受到损伤。突触损伤一般无法完全恢复，这可能是导致听神经最终死亡的重要原因之一。我们之前发现在噪声损害后的耳蜗中，神经营养因子NT-3能够有效促进带状突触的再生和听力的恢复，而另一相似的神经营养因子BDNF却不能促进突触再生，表明NT-3能够特异性的激活突触的再生机制。本项目中，我们将建立噪声性和老年性突触损伤和听力损失的小鼠模型，深入研究NT-3特异性调控突触再生的下游靶点和分子机制。此外，我们还将验证NT-3及其下游靶点是否能够同样促进老龄耳蜗中的突触再生。通过此项研究，我们不仅能够为神经感应性耳聋提供新的治疗靶点，而且能揭示突触重塑和再生的分子机制，为其他的突触损伤疾病提供新的出路。

耳蜗带状突触的退行是包括噪声性和老年性等耳聋的重要病理因素。本项目拟利用遗传工程小鼠模型，探究耳蜗带状突触的发育、退行和再生机制，研究神经生长因子、巨噬细胞等调控带状突触可塑性的作用，从而揭示感音神经性耳聋的治疗新策略。在本项目中，申请人团队揭示了耳蜗带状突触在听力损失和平衡障碍中的一致性重要作用（Cold Spring Harb Perspect Med 2020；Front Aging Neurosci 2019） ，说明突触退行是介导耳蜗和前庭功能障碍的共同机制。我们还阐明了耳蜗带状突触的出生后发育规律，并揭示了巨噬细胞在带状突触发育中的作用（Front Cell Neurosci 2021）。此外，我们还将耳蜗胶质细胞体外转分化位神经元，为耳蜗神经元和突触再生治疗耳聋提供了研究基础（Front Cell Dev Biol 2021）。最后，本项目的拓展课题还发现了新的耳聋相关基因、机制与治疗（Cell Rep 2020；Plos Genet 2020）。综上所述，在本项目中，我们阐述了耳蜗带状突触发育和退行的规律和机制，揭示了新的耳聋基因与机制，为将来的耳聋临床诊治提供了新的思路。