小鼠耳蜗噪声性听力损失的蛋白质组学特征。

文献信息

中文摘要

背景： 听力损失影响全球超过15亿人，并带来重大的社会、教育和经济后果。尽管遗传学研究已鉴定出众多与听力损失相关的基因，但伴随噪声性听力损失（NIHL）发生的分子变化仍不完全清楚。方法：我们使用纳升液相色谱-串联质谱（nano-LC-MS/MS）和整合生物信息学工作流程，表征了成年小鼠在损伤性噪声暴露后的耳蜗蛋白质组。结果：对正常听力与NIHL耳蜗的比较分析鉴定出1742种蛋白质，以及一个由80种蛋白质组成的NIHL相关特征，其中包括49种定量定义的差异丰度蛋白质和31种条件特异性蛋白质。这些蛋白质被组织为五个功能组，涵盖代谢与线粒体功能、蛋白质合成与核糖核蛋白复合物、结构与突触组织、细胞极性与细胞骨架重塑，以及调节与应激响应功能。代表性改变包括：HSPA9（一种参与蛋白质稳态的线粒体伴侣蛋白）减少；RNA相关蛋白PRMT1和CIRBP发生变化；HAPLN1（与细胞外基质组织相关）减少；MAP2K2（一种与细胞极性相关的信号蛋白）改变；以及SYNJ2增加。与一个独立的耳蜗蛋白质组数据集的比较鉴定出80种蛋白质中有39种失调，其中22种显示一致的方向性变化。单细胞转录组图谱为80个蛋白质相关基因中的74个提供了细胞背景，而人类遗传和疾病注释支持对与听力或耳表型相关的选定蛋白质进行优先排序。结论：总之，这些发现定义了噪声暴露耳蜗的蛋白质组景观，并确定了用于进一步研究NIHL的分子候选物和细胞过程。

英文摘要

Hearing loss affects over 1.5 billion people worldwide and has substantial social, educational, and economic consequences. Although genetic studies have identified numerous hearing-loss-associated genes, the molecular changes accompanying noise-induced hearing loss (NIHL) remain incompletely understood. We characterized the adult mouse cochlear proteome following damaging noise exposure using nano-LC-MS/MS and an integrative bioinformatics workflow. Comparative profiling of normal-hearing and NIHL cochleae identified 1742 proteins and an 80-protein NIHL-associated signature comprising 49 quantitatively defined differentially abundant proteins and 31 condition-specific proteins. These proteins were organized into five functional groups encompassing metabolic and mitochondrial function, protein synthesis and ribonucleoprotein complexes, structural and synaptic organization, cell polarity and cytoskeletal remodeling, and regulatory and stress-responsive functions. Representative alterations included reduced HSPA9, a mitochondrial chaperone involved in protein homeostasis; changes in the RNA-associated proteins PRMT1 and CIRBP; reduced HAPLN1, associated with extracellular matrix organization; and altered MAP2K2, a signaling protein related to cell polarity; and increased SYNJ2. Comparison with an independent cochlear proteomic data set identified 39 of the 80 proteins as dysregulated, with 22 showing concordant directional changes. Single-cell transcriptomic mapping provided cellular context for 74 of the 80 protein-associated genes, while human genetic and disease annotations supported the prioritization of selected proteins associated with hearing or ear phenotypes. Together, these findings define a proteomic landscape of the noise-exposed cochlea and identify molecular candidates and cellular processes for further investigation of NIHL.