Modulation of the Rate of Retinal Degeneration in T17M RHO Mice by Reprogramming the Unfolded Protein Response.
Modulation of the Rate of Retinal Degeneration in T17M RHO Mice by Reprogramming the Unfolded Protein Response.
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DOI：
10.1007/978-1-4614-3209-8_58
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发表时间：
2014-01-01
期刊：
影响因子：
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通讯作者：
Gorbatyuk, Marina
中科院分区：
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作者：
Choudhury, Shreyasi;Nashine, Sonali;Gorbatyuk, Marina
本研究的目的是验证通过调节促凋亡caspase-7和CHOP蛋白来重编程UPR是否是减缓ADRP小鼠视网膜变性速率的有效方法。为了实现我们的目标，我们创建了T17 M RHO CASP 7和T17 M RHO CHOP小鼠，以通过ERG、SD-OCT、组织学和蛋白质印迹分析来研究T17 M RHO视网膜中CASP 7或CHOP消融的影响。暗视ERG表明，与对照相比，T17 M RHO视网膜中CASP 7的消融导致光感受器功能的显著保留。令人惊讶的是，T17 M RHO小鼠中促凋亡CHOP蛋白的消融导致更严重形式的视网膜变性。SD-OCT和组织学结果与ERG数据一致。进一步的分析表明，通过UPR的重编程，T17 M RHO光感受器变性的结构和功能得以保留或加速发生。此外，CASP 7消融导致cJUN介导的细胞凋亡的抑制，而CHOP消融诱导HDAC增加。因此，普遍定期审议的操作需要仔细检查，以达到治疗效果。
The goal of this study is to validate whether reprogramming of the UPR via modulation of pro-apoptotic caspase-7 and CHOP proteins could be an effective approach to slow down the rate of retinal degeneration in ADRP mice. In order to pursue our goal we created the T17M RHO CASP7 and T17M RHO CHOP mice to study the impact of the CASP7 or CHOP ablations in T17M RHO retina by ERG, SD-OCT, histology and western blot analysis. The scotopic ERG demonstrated that the ablation of the CASP7 in T17M RHO retina leads to significant preservation of the function of photoreceptors compared to control. Surprisingly, the ablation of pro-apoptotic CHOP protein in T17M RHO mice led to a more severe form of retinal degeneration. Results of the SD-OCT and histology were in agreement with the ERG data. The further analysis demonstrated that the preservation of the structure and function or the acceleration of the onset of the T17M RHO photoreceptor degeneration occurred via reprogramming of the UPR. In addition, the CASP7 ablation leads to the inhibition of cJUN mediated apoptosis, while the ablation of CHOP induces an increase in the HDAC. Thus, manipulation with the UPR requires careful examination in order to achieve a therapeutic effect.