CYLD介导RIP1去泛素化修饰参与调控螺旋神经元存活的机制研究

Sensorineural hearing loss is common diseases of otology, caused by the death of terminal cells of cochlear hair cells and spiral ganglion cells, but there is no effective treatment. The prevention and treatment of sensorineural hearing loss has been a hot research. Ubiquitin modification as eukaryotic animal protein degradation of the main mechanisms involved in machine within a number of molecular events such as neural degeneration. However, the mechanism of sensorineural hearing loss has not yet been systematically. Our previous studies have demonstrated for the first time that programmed necrosis and apoptosis are involved in the process of the death of cochlear spiral ganglion neurons. In addition, we also found that the death of spiral ganglion neurons and regulation in apoptosis and necrosis pathway plays an important role of receptor interactions to the elevated Receptor interacting protein 1 (RIP1) the expression level of, and to ubiquitin conjugating enzyme regulation enzyme CYLD also up-regulated the expression, the mechanism is not clear. These results suggest that RIP1 may be involved in the regulation of spiral neuron necrosis. Furthermore, this study intends to from the CYLD to rip1 ubiquitination involved in neuronal death spiral brand-new angle, use of CYLD siRNA, in-depth analysis of CYLD silencing effect of spiral ganglion neurons death of biological effects, system to elucidate molecular signal pathway, and to explore the CYLD inhibitors for treatment.

感音神经性聋是耳科常见病，由发育终末细胞：耳蜗毛细胞和螺旋神经元死亡引起永久性聋，目前尚无有效治疗。因而感音神经性聋的防治一直是国内外耳科研究的热点。泛素化修饰作为真核动物蛋白降解的主要途径，参与机体内多种分子事件如神经退化等，然而其在感音神经性聋中的作用机制尚未系统展开。我们前期研究首次证实在耳蜗螺旋神经元死亡过程中，程序性坏死和凋亡共同参与。此外，我们还发现在凋亡、程序性坏死通路都发挥重要作用的受体相互作用蛋白1（RIP1）表达水平在螺旋神经元损伤后升高，其去泛素化酶调控酶CYLD表达同样上调，其机制不清。这些结果表明RIP1去泛素化修饰可能参与调控螺旋神经元存活。进而，本研究拟从CYLD去泛素化RIP1参与调控螺旋神经元存活的新角度，利用CYLD-siRNA/Adv-CYLD，深入分析CYLD影响螺旋神经元存活的机制及阐明相关分子通路，探寻可能的治疗靶点，为感音神经性聋治疗提供新策略。

感音神经性耳聋是耳科常见病，严重影响患者的生活质量，加重社会经济负担。耳蜗毛细胞和螺旋神经节神经元的死亡导致永久性耳聋，目前尚无有效的治疗方法。RIP1作为调控细胞存活和死亡的上游因子，在调控细胞凋亡、坏死和存活、决定细胞存活或凋亡/坏死的途径中发挥着重要作用。泛素化作为真核生物蛋白质降解的主要途径，参与机体的多种分子事件，如神经退行性疾病。CYLD是一种细胞去泛素酶，通过消除RIP1的多泛素连接，在调节细胞存活、肿瘤发生和细胞增殖过程中促进细胞死亡。然而，迄今为止，CYLD介导的RIP1二肽化与螺旋神经节神经元死亡的关系尚未得到研究。因此，本研究旨在阐明CYLD介导的RIP1二氢基化在螺旋神经节神经元存活调控中的作用。首先检测药物性耳聋大鼠模型中RIP1和CYLD的表达水平，然后检测转染CYLD-siRNA后大鼠模型的听力、SGNs形态学和SGNs计数，目的阐明CYLD参与螺旋神经节神经元存活调控的机制及相关分子途径，为感音神经性耳聋的治疗提供新的靶点和策略。