Attenuation of vision loss and delay in apoptosis of photoreceptors induced by proinsulin in a mouse model of retinitis pigmentosa
Attenuation of vision loss and delay in apoptosis of photoreceptors induced by proinsulin in a mouse model of retinitis pigmentosa
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DOI：
10.1167/iovs.08-2182
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发表时间：
2008-09-01
影响因子：
4.4
通讯作者：
de la Rosa, Enrique J.
中科院分区：
文献类型：
--
作者：
Corrochano, Silvia;Barhoum, Rima;de la Rosa, Enrique J.
目的。色素性视网膜炎 (RP) 是一组异质性遗传性疾病，可导致失明，且尚无有效治疗方法。光感受器细胞凋亡是该疾病动物模型的一个共同特征。因此，作者研究了胰岛素原（一种在视网膜发育过程中活跃的抗凋亡分子）的治疗潜力。在混合 C57BL/6:SJL 背景中产生在骨骼肌中表达人胰岛素原 (hPi) 的转基因小鼠，并与 C57BL/6 背景回交。建立了两个独立的转基因小鼠谱系，其中肌肉中的 hPi 产生是组成型的并且不受葡萄糖水平的调节。使用商业 ELISA 试剂盒测定血清、肌肉和视网膜中的 hPi 水平，通过视网膜电图 (ERG) 记录评估视觉功能，并通过 TUNEL 评估程序性细胞死亡。免疫组织化学用于评估视网膜结构保存和氧化损伤。结果。根据 ERG 记录确定，rd10 视网膜变性小鼠模型中 hPi 的转基因表达导致视力延长，其方式与转基因表达水平相关。这种视觉恶化的减弱与光感受器细胞凋亡的延迟以及视网膜细胞结构（尤其是视锥细胞结构）的保存相关。结论。这些结果为对抗色素性视网膜炎的可能疗法提供了新的基础，并为表征视网膜神经变性进展机制提供了新的工具。
PURPOSE. Retinitis pigmentosa (RP) is a heterogeneous group of inherited conditions that lead to blindness and for which there is no effective therapy. Apoptosis of photoreceptors is a common feature in animal models of the disease. Thus, the authors studied the therapeutic potential of proinsulin, an antiapoptotic molecule active during retinal development.METHODS. Transgenic mice expressing human proinsulin (hPi) in the skeletal muscle were generated in a mixed C57BL/6: SJL background and were back-crossed to a C57BL/6 background. Two independent lineages of transgenic mice were established in which hPi production in muscle was constitutive and not regulated by glucose levels. hPi levels in serum, muscle, and retina were determined with a commercial ELISA kit, visual function was evaluated by electroretinographic (ERG) recording, and programmed cell death was assessed by TUNEL. Immunohistochemistry was used to evaluate retinal structure preservation and oxidative damage.RESULTS. Transgenic expression of hPi in the rd10 retinal degeneration mouse model led to prolonged vision, as determined by ERG recording, in a manner that was related to the level of transgene expression. This attenuation of visual deterioration was correlated with a delay in photoreceptor apoptosis and with the preservation of retinal cytoarchitecture, particularly that of the cones.CONCLUSIONS. These results provide a new basis for possible therapies to counteract retinitis pigmentosa and a new tool to characterize the mechanisms involved in the progress of retinal neurodegeneration.