内耳毛细胞组蛋白乙酰化在噪声性耳聋中的变化及对其干预效果的研究

Noise-induced hearing loss(NIHL) always severely interfere with patients' life quality.So far as the mechanisms of NIHL, oxidative stress does the big part.Most of current research works focus on the identification of apoptosis pathways and the regulation of associated signaling molecules on the translation-level, less attention is paid on the regulation mechanism on the transcription-level.Some proof have showed that chromatin histone acetylation can do effect on survive and apoptosis through the influence on transcription of proteins,we propose the hypothesis of "noise-oxidative stress-acetylation imbalance-proteins associated with apoptosis change-apoptosis of functional cells".In our study,a fundamental data pattern about the histone acetylation change in NIHL is needed in the first part,the contributive histone subtypes,acetylases and deacetylases need to be distinguished. secondly we will try to counteract the NIHL with the applying of histone deacetylase inhibitor(HDACi)(endogenic or exogenetic)which have involved in clinical trials for the treatment of cancer;finally, the relationship between acetylation and oxidative stress or apoptosis pathways will be studied for the advanced understand of the mechanism. In our study, we aim to understand the effect of histone acetylaiton involved in the mechanism of NIHL and provide a new potential aspect we can develop to prevent and treat NIHL.

噪声所导致的听力下降严重影响患者的生活质量。噪声性聋的发病机制主要与内耳的氧化应激损伤有关。目前的研究主要集中于凋亡通路的识别及其相关信号分子的蛋白水平的调控上，对影响其转录水平的调控机制涉及不多。已有研究证实染色质组蛋白乙酰化的改变可以通过调节相关蛋白的转录水平而参与对细胞生存和凋亡的调控。因此我们提出"噪声-氧化应激-乙酰化失衡-凋亡相关蛋白改变-功能细胞凋亡"的假说，拟检测噪声性聋动物模型耳蜗毛细胞组蛋白的乙酰化改变；分析内耳毛细胞乙酰化-去乙酰化平衡失调的特点；采用已进入临床试验阶段的内源性及外源性去乙酰化酶抑制剂对其乙酰化改变进行干预，研究其对噪声性聋的防治效果，推动转化医学的进程；同时探索噪声性聋内耳乙酰化改变与氧化应激及凋亡通路相关蛋白之间的关系；从而为噪声性聋的研究和防治提供更多思路。

噪声性耳聋严重影响患者的生活质量，既往的研究表明氧化应激是其主要的损伤机制。目前有研究表明抑制内耳细胞组蛋白去乙酰化有利于听力的保护，但是其是否参与噪声性耳聋以及其潜在的机制不明。因此我们研究了噪声性耳聋豚鼠模型与对照组内耳细胞中乙酰化组蛋白（H3‑AcK9）及组蛋白去乙酰化酶(HDAC1)的表达；评估腹腔注射应用去乙酰化酶抑制剂丁酸钠对噪声性耳聋的保护作用；此外我们还评估了内耳细胞组蛋白乙酰化与氧化应激之间的关系。结果显示丁酸钠可以降低噪声性耳聋动物模型的永久性阈移及毛细胞损伤；使用丁酸钠后，毛细胞、血管纹及边缘细胞的细胞核内乙酰化组蛋白（H3‑AcK9）增加，组蛋白去乙酰化酶受抑制，但是螺旋神经节细胞内无明显变化；此外，丁酸钠还可以降低噪声性耳聋豚鼠模型中外毛细胞氧化应激产物3-硝基酪氨酸的表达。这些研究表明丁酸钠能够通过抑制组蛋白去乙酰化酶及减轻内耳细胞的氧化应激作用而减少噪声诱导的听力下降，因此丁酸钠可能有利于临床对噪声性耳聋的预防和治疗。