【作者】 李海霞；

【导师】 刘敏；

【作者基本信息】 山东师范大学 ， 细胞生物学， 2021， 硕士

【摘要】 早产儿视网膜病变(retinopathy of prematurity,ROP)在全世界儿童致盲病因中占主导地位。氧气的改变(早产儿首先高氧供给,之后恢复到正常氧气环境中)导致视网膜血管异常增生以及随后的视网膜脱落,是ROP发病的主要诱因。而ROP的治疗手段,主要针对干预异常增生的血管,比如激光治疗和冷冻疗法,还有抗血管内皮生长因子(anti-vascular endothelial growth factor,anti-VEGF)治疗。但这些治疗方法,存在会对正常组织造成损伤影响视力,复发率较高和有副作用的问题。感光细胞是一种负责把光信号转变为神经信号,并最终传递到大脑的神经细胞。研究表明纤毛结构或者功能的异常会引起感光细胞受损甚至失明。然而,纤毛在ROP发病进程中是否也发挥作用并不清楚。目前,研究ROP的常用模型为高氧诱导视网膜病变(oxygen-induced retinopathy,OIR)小鼠模型,本论文利用该模型探究ROP的发病机制和相关分子机制,并寻找一种新的有效方案预防或治疗ROP。本论文利用OIR小鼠模型来模拟ROP,探究ROP的发病机制。通过免疫荧光染色等一系列实验发现,OIR小鼠视网膜感光细胞的感光层OS相比于对照组明显变薄,纤毛明显缩短。进一步对纤毛相关蛋白进行研究,结果发现HDAC6明显上调,通过下一步的机制探究,发现了与HDAC6(histone deacetylase 6)互作的凋亡信号调节激酶1(apoptosis signal-regulating kinase 1,ASK1)。高氧致使ASK1激活,进而HDAC6在纤毛上聚集,最终促使HDAC6介导的纤毛解聚。更重要的是,利用ASK1的小分子抑制剂,能够有效地保护小鼠视网膜免受高氧刺激带来的损伤。这些发现阐明了ASK1在ROP中的病理学功能和分子机制,而靶向ASK1的小分子抑制剂也有望成为预防ROP的新的临床药物。更多还原

【Abstract】 Retinopathy of prematurity(ROP)is the leading cause of blindness in children worldwide.The abnormal growth of retinal blood vessels and subsequent retinal detachment caused by the change of oxygen(exposure of infants to high oxygen and then restored to a normal oxygen environment)are considered as the main causes of ROP.The treatment of ROP is mostly aimed at the abnormal growth of blood vessels,such as laser therapy,cryotherapy and the anti-vascular endothelial growth factor agents.However,these treatment methods are associated with tissue injury that leading to partial loss of vision,high recurrence rate and potential side effects.Photoreceptors are a type of nerve cells that are responsible for converting light signals into nerve signals,and ultimately transmitted to the brain.Studies have shown that abnormalities in the structure or function of photoreceptor cilium could lead to photoreceptor degeneration and even visual loss.However,it is unclear whether photoreceptor cilium could also participate in the degeneration of ROP.The mouse model of oxygen-induced retinopathy(OIR)is a well-established model to study ROP.In this study,we used this model to clarify the pathogenesis and molecular mechanisms of ROP,and explore a new and effective therapy for preventing ROP.Here,using OIR mouse model for ROP,through a series of experiments such as immunofluorescence staining,we found that the length of OS in OIR mice was significantly shorter than the control group,and the photoreceptor cilium were significantly reduced.Further study showed that HDAC6 was up-regulated.Through the next step of exploring the mechanism,we found that apoptosis signal-regulating kinase 1(ASK1) interacted with HDAC6.Oxygen changes induced the activation of ASK1 and the collection of HDAC6 on the photoreceptor cilium.Leading to photoreceptor cilium disassembly mediated by HDAC6.More importantly,using small molecule inhibitors targeting ASK1 could effectively protect the photoreceptor degeneration caused by oxygen changes.These findings clarify the pathological function and molecular mechanism of ASK1 mediated photoreceptor cilium disassembly in ROP,and demonstrate a potential value of the inhibitors targeting ASK1 to prevent ROP.更多还原