Claudin11在铅导致听力损伤中的作用及其机制研究

Hearing loss, a kind of serious disability, could deteriorate the physical health, mental health and social life. According to previous survey. Lead is an important risk factors for hearing loss and it could cause hearing nerves damage. However, the specific regulatory mechanism for lead toxicity has not yet been elucidated. Our preliminary study results show that chronic lead exposure could cause rat auditory system injury, which is characterized by increased threshold, permeability change of BLB (blood labyrinth barrier). Several other studies have shown that tight junction protein Claudin11 is the key regulatory proteins for BLB structure. The regulatory mechanism for hearing loss caused by the lead still needs further research. On these bases, this project is proposed to reveal the core role of Claudin11 in the lead-induced damage of BLB. What’s more, it will explore Claudin11 regulation mechanism from the perspective of microRNA. The results will lead to clarify the theoretical basis for damage mechanism of BLB and auditory function, and to seek protection for lead-induced hearing loss.

听力损伤严重影响身心健康和社会生活，是一类重要残疾，调查显示环境因素在致听力损伤过程中发挥重要作用。铅做为一种强神经毒物，是导致听力系统损伤的高风险因素之一，但铅暴露对于听力系统的调控机制目前尚未阐明。课题组前期研究结果表明，慢性铅暴露可以引起大鼠听觉系统损伤，表现为听阈增高、血迷路屏障（BLB）通透性变化等，但损伤的具体机制仍未明确。Claudin11作为BLB紧密连接结构中的关键蛋白，其在铅暴露引起的听力损伤中的具体调控机制尚待进一步研究。本项目拟在前期研究基础上，以Claudin11在铅诱导BLB开放中的作用为核心，从MicroRNA角度探讨其对Claudin11的调控机制，研究结果将为阐明铅对BLB及听觉功能损伤机理奠定理论基础，对寻求铅致听力损伤防护措施具有重要意义。

铅在工业发展中发挥着重要作用，同时也是一种主要的环境毒物，可诱发严重的神经毒性。以往的研究表面，母亲接触铅可导致后代神经发育异常，包括不可逆转的听力损失，但其机制尚未明确阐明。由于紧密蛋白缺乏引起的紧密连接障碍功能是听力功能下降的重要因素之一，所以本课题重点关注了在耳蜗中特异性表达的紧密连接蛋白Claudin11。为探讨慢性铅暴露对子代听力的影响，本课题建立了成年妊娠大鼠铅暴露模型，暴露时间持续5个月。实验测定了所有动物的听力水平，以及在血管纹、膜和基底膜中claudin11的表达情况。与以往的研究结果不同，本实验在大鼠耳蜗血管纹中claudin11未被明显检测到。同时结果显示，铅暴露28d后，大鼠耳蜗蜗轴和基底膜中claudin11的表达显著降低，而对成年大鼠有轻微损伤。综上所述，我们发现母代暴露于铅环境下，通过改变血管纹、蜗轴和基底膜中claudin11的表达，从而导致子代听力异常，从而导致耳蜗功能障碍。

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