Trx调控ASK1-JNK/p-38凋亡信号通路异常在老年性聋中作用机制的研究

Previous studies indicated that oxidative stress plays a pivotal role in the pathological process of presbycusis. However, the mechanisms involved in presbycusis still remain elusive. Thioredoxin, a small molecular protein, is important for cellular redox balance. It has been shown to play a key role in regulating cellular reactive oxygen species (ROS) homeostasis and anti-apoptosis. Our preliminary study demonstrated that the level of Trx expression was significantly decreased, while the activity of ASK1-JNK/p-38 apoptosis signal pathway was significantly increased in the auditory cortex of 10-month-old mimetic aging rat. Furthermore, we found that oxidative stress developed. These results indicated that the decrease of Trx expression might play an important role, via the mediation of activity of ASK1-JNK/p-38 signal pathway, in the accumulation of oxidative stress in the organs of presbycusis. However, the mechanisms by which Trx mediated abnormal regulation of ASK1-JNK/p-38 apoptosis signal pathway involved in presbycusis still remain unclear. This study aims to explore the possible mechanism of Trx mediated abnormal regulation of ASK1-JNK/p-38 apoptosis signal pathway involved in presbycusis using mimetic aging rat and cell models. In this research, a variety of methods, such as molecular biology and morphology are used. This research may shed light on providing a new approach to combat presbycusis.

研究表明老年性聋与氧化应激密切相关，然而该病的具体发病机制尚不明确。硫氧还蛋白（Trx）是一类位于细胞内的调节氧化还原的小分子蛋白,在抵御氧化应激与细胞凋亡方面发挥着极为重要的作用。我们利用D-半乳糖诱导的拟老化大鼠模型，初步研究发现在10月龄拟老化大鼠听皮层组织中氧化应激产物明显增加，Trx表达显著下降而ASK1-JNK/p-38信号通路活性明显增加。我们推测“Trx水平下降，对ASK1-JNK/p-38信号通路抑制作用降低”可能是老年性聋患者听觉器官氧化应激蓄积的新机制。但Trx调控ASK1-JNK/p-38信号通路异常在老年性聋的具体作用机制尚未明确。在本课题中，我们将从动物-细胞-细胞亚结构-分子四个层次，应用分子生物学，形态学等方法研究Trx调控ASK1-JNK/p-38信号通路异常在老年性聋中的具体作用机制。为老年性聋的预防与治疗提供新途径与思路。

研究表明老年性聋与氧化应激密切相关，然而该病的具体发病机制尚不明确。硫氧还蛋白2（Trx2）是一类位于细胞内的调节氧化还原的小分子蛋白,在抵御氧化应激与细胞凋亡方面发挥着极为重要的作用。我们利用D-半乳糖诱导的拟老化大鼠模型，研究发现在10月龄拟老化大鼠听皮层组织中氧化应激产物明显增加。我们推测“Trx2水平下降，对ASK1-JNK/p-38信号通路抑制作用降低”可能是老年性聋患者听觉器官氧化应激蓄积的新机制。在本课题中，我们利用在体与离体实验，通过半乳糖诱导的衰老模型来研究由Trx2表达下降引起的ASK1-JNK/p-38信号通路异常中的作用。结果证明，拟老化组听皮层组织Trx2显著下降，而ASK1-JNK/p-38信号通路活性增加，并且我们发现，敲除细胞Trx2后，能够激活ASK1-JNK/p-38信号通路，最终导致细胞内ROS水平增加，促使细胞衰老，凋亡和死亡。