Abnormal mTORC1 signaling leads to retinal pigment epithelium degeneration
Abnormal mTORC1 signaling leads to retinal pigment epithelium degeneration
复制标题
mTORC1信号异常导致视网膜色素上皮变性
DOI：
10.7150/thno.26281
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhao, Chen
中科院分区：
文献类型：
--
作者：
Huang, Jiancheng;Gu, Shun;Zhao, Chen
视网膜色素上皮（RPE）变性可能参与多种视网膜变性疾病的发病机制。 mTORC1 信号传导被证明是许多生物过程和疾病进展的关键调节因子。在这项研究中，我们旨在研究 mTORC1 信号在 RPE 变性中的作用。方法：采用蛋白质印迹法检测 RPE 变性过程中 mTORC1 的表达模式。 Cre-loxP系统用于生成RPE特异性mTORC1激活小鼠。通过眼底、免疫荧光染色、透射电子显微镜和靶向代谢组学分析来确定 mTORC1 激活对体内 RPE 变性的影响。通过视网膜电图、谱域光学相干断层扫描和组织学实验来确定 mTORC1 激活对体内脉络膜和视网膜功能的影响。结果：mTORC1 的 RPE 特异性激活导致 RPE 变性，表现为 RPE 特异性标记物的丢失、细胞连接完整性受损和细胞内脂滴积累。 RPE变性进一步导致脉络膜和视网膜功能异常。用雷帕霉素抑制 mTORC1 信号传导可以部分逆转 RPE 退化。靶向代谢组学分析进一步揭示mTORC1激活影响RPE中嘌呤、羧酸和烟酸的代谢。结论：本研究表明mTORC1信号的异常激活会导致RPE退化，这可能为RPE功能障碍相关疾病的治疗提供一个有前景的靶点。
Retinal pigment epithelial (RPE) degeneration is potentially involved in the pathogenesis of several retinal degenerative diseases. mTORC1 signaling is shown as a crucial regulator of many biological processes and disease progression. In this study, we aimed at investigating the role of mTORC1 signaling in RPE degeneration. Methods: Western blots were conducted to detect mTORC1 expression pattern during RPE degeneration. Cre-loxP system was used to generate RPE-specific mTORC1 activation mice. Fundus, immunofluorescence staining, transmission electron microscopy, and targeted metabolomic analysis were conducted to determine the effects of mTORC1 activation on RPE degeneration in vivo. Electroretinography, spectral-domain optical coherence tomography, and histological experiments were conducted to determine the effects of mTORC1 activation on choroidal and retinal function in vivo. Results: RPE-specific activation of mTORC1 led to RPE degeneration as shown by the loss of RPE-specific marker, compromised cell junction integrity, and intracellular accumulation of lipid droplets. RPE degeneration further led to abnormal choroidal and retinal function. The inhibition of mTORC1 signaling with rapamycin could partially reverse RPE degeneration. Targeted metabolomics analysis further revealed that mTORC1 activation affected the metabolism of purine, carboxylic acid, and niacin in RPE. Conclusion: This study revealed that abnormal activation of mTORC1 signaling leads to RPE degeneration, which could provide a promising target for the treatment of RPE dysfunction-related diseases.