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Inhibition of mTOR signaling by rapamycin protects photoreceptors from degeneration in rd1 mice

Jia-Liang Yang Tong-Dan Zou Fang Yang Zheng-Lin Yang Hou-Bin Zhang

Jia-Liang Yang, Tong-Dan Zou, Fang Yang, Zheng-Lin Yang, Hou-Bin Zhang. Inhibition of mTOR signaling by rapamycin protects photoreceptors from degeneration in rd1 mice. Zoological Research, 2021, 42(4): 482-486. doi: 10.24272/j.issn.2095-8137.2021.049
Citation: Jia-Liang Yang, Tong-Dan Zou, Fang Yang, Zheng-Lin Yang, Hou-Bin Zhang. Inhibition of mTOR signaling by rapamycin protects photoreceptors from degeneration in rd1 mice. Zoological Research, 2021, 42(4): 482-486. doi: 10.24272/j.issn.2095-8137.2021.049

雷帕霉素抑制mTOR信号通路可延缓rd1小鼠视网膜变性

doi: 10.24272/j.issn.2095-8137.2021.049

Inhibition of mTOR signaling by rapamycin protects photoreceptors from degeneration in rd1 mice

Funds: This study was supported by the National Precision Medicine Project (2016YFC0905200) (Z.Y. & H.Z.), National Natural Science Foundation of China (81570882 (H.Z.), 81770935 (H.Z.)), Department of Science and Technology of Sichuan Province, China ((2020YJ0445) (H.Z.), 2020ZYD037 (Z.Y)), and CAMS Innovation Fund for Medical Sciences (2019-I2M-5-032) (Z.Y.)
More Information
  • 摘要: 视网膜色素变性(RP)是一种遗传性视网膜变性疾病。RP最初影响视杆细胞的功能,随着病情的发展,视锥细胞也会受损,最终导致完全失明。该病目前没有有效的治疗方法。rd1小鼠是一种被广泛用于研究视网膜变性的小鼠模型。rd1小鼠携带天然的Pde6b基因无义突变,其视杆细胞缺乏有活性的PDE6酶,引起胞内cGMP水平升高,更多的Ca2+通道打开,使大量的Ca2+进入视杆细胞,导致视网膜感光细胞迅速发生变性。以前的研究表明,胞内高水平的Ca2+会激活mTOR信号通路,该通路感知细胞内外养分的变化,调节蛋白和脂类物质的合成,并调控细胞的凋亡和自噬。在本研究中我们发现rd1小鼠感光细胞中mTOR信号通路被激活。P10的rd1小鼠(视网膜发生明显变性之前)经玻璃体腔注射mTOR的抑制剂雷帕霉素治疗后,视网膜变性显著延缓,视网膜功能得到显著改善。雷帕霉素的治疗作用可能通过促进细胞自噬实现。综上,雷帕霉素有望成为一种治疗视网膜变性的药物。
  • Figure  1.  Inhibition of retinal degeneration and preservation of cone function in rd1 mice treated with rapamycin

    P10 rd1 mice were treated by intravitreal injection of 10 µmol/L (Rapa10), 25 µmol/L (Rapa25), 50 µmol/L rapamycin (Rapa50), or vehicle control (DMSO). A–D: Mice were analyzed 20 h after treatment. For each rapamycin-treated group, including vehicle control, n=3 mice/group. E–G: Mice were analyzed 6 days after treatment. For each rapamycin-treated group, including vehicle control, n=4 mice/group. A: Representative confocal images showing TUNEL signals in photoreceptors. Nuclei were stained by DAPI. Arrowheads indicate TUNEL-positive nuclei. Scale bar: 20 µm. B: Quantification of TUNEL-positive nuclei in entire retinal sections corresponding to images shown in (A). Data are mean±standard deviation (SD). **: P<0.01; ***: P<0.001. C: Western blot analysis was used to detect expression of apoptotic protein cleaved caspase 3. GAPDH was used as a loading control. D: Quantification of western blot signals shown in (C). Data are mean±SD. ***: P<0.001; ****: P<0.0001. E: Representative individual confocal images of retinal sections stained by DAPI (blue). Scale bar: 20 μm. ONL, outer nuclear layer; INL, inner nuclear layer. F: Measurement of ONL thickness along central meridian at 10 locations on dorsal to ventral axis in mouse eyes 6 days after treatment. G: Photopic electroretinograms (ERGs, recorded at 50 cd·s/m2) of rd1 mice 6 days after rapamycin treatment. All quantification data are expressed as mean±SD. *: P<0.05; **: P<0.01; ***: P<0.001; ****: P<0.0001; ns: No significance P>0.05.

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出版历程
  • 收稿日期:  2021-04-17
  • 录用日期:  2021-06-30
  • 网络出版日期:  2021-07-05
  • 刊出日期:  2021-07-18

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