噪声诱导的隐匿性听力损失（Noise-induced Hidden Hearing Loss, NIHHL）是指噪声暴露后个体表现为听功能受损，但无永久性阈移，其发生机制不明，是目前耳科学领域研究热点。研究证明噪声可导致耳蜗内活性氧大量产生。我们发现NIHHL小鼠耳蜗内毛细胞和螺旋神经节细胞中存在线粒体损伤；过表达SIRT3的体外螺旋神经节细胞可有效对抗线粒体DNA氧化损伤。因此我们提出假设：SIRT3可通过调节耳蜗感觉和神经细胞活性氧产生进而调控NIHHL的发生发展，并可作为NIHHL关键干预靶点。本项目拟在NIHHL动物模型中研究SIRT3对线粒体蛋白乙酰化、线粒体氧化损伤、带状突触及听功能的调控作用及机制。进而利用SIRT3激动剂对NIHHL小鼠进行干预，利用SIRT3基因过表达对遭受噪声二次暴露的NIHHL小鼠进行线粒体靶向治疗。本项目将为NIHHL发病机制和临床干预研究奠定基础。

Noise-induced hidden hearing loss (NIHHL) has become a hot topic in the field of otology in recent years. NIHHL refers to any functional impairment seen in subjects with noise exposing history but no permanent threshold shift. The pathological mechanisms of NIHHL are largely unknown. A recent study shows that overexpression of mitochondrial deacetylase SIRT3 can significantly protect noise-induced hearing loss. Our previous study found that overexpression of SIRT3 was able to prevent H2O2-induced oxidative damage of mitochondrial DNA of cochlear spiral ganglion cells (SGCs). Since mitochondrial deacetylase SIRT3 plays an important role in maintaining post-synaptic terminals and synaptic transmission, we hypothesize that inhibition of reactive oxygen species (ROS) mediated through SIRT3 in SGCs and inner hair cells (IHCs) can prevent NIHHL by promoting repair of post-synaptic terminals and maintaining IHC ribbon synapses and that SIRT3 might be a key therapeutic target of NIHHL. In this study, we will detect the acetyl levels of mitochondrial proteins, mitochondrial function and ROS-induced damage in mouse models imitating NIHHL. We will generate three lines of knockout mice to examine the pathways of NIHHL. Finally, we will explore the strategies to treat NIHHL by round window application of a chitosan-SIRT3 agonist. Adenovirus-mediated SIRT3 inoculation through posterior semicircular canal of the cochlea will be used to determine whether overexpression of SIRT3 will protect profound hearing loss induced by a second noise exposure. Thus, our project is expected to provide mechanistic understanding of NIHHL and lay foundation for clinical intervention through manipulation of the expression of SIRT3.