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杨佳良, 邹同丹, 杨芳, 杨正林, 张侯斌. 2021: 雷帕霉素抑制mTOR信号通路可延缓rd1小鼠视网膜变性. 动物学研究, 42(4): 482-486. DOI: 10.24272/j.issn.2095-8137.2021.049
引用本文: 杨佳良, 邹同丹, 杨芳, 杨正林, 张侯斌. 2021: 雷帕霉素抑制mTOR信号通路可延缓rd1小鼠视网膜变性. 动物学研究, 42(4): 482-486. DOI: 10.24272/j.issn.2095-8137.2021.049
Jia-Liang Yang, Tong-Dan Zou, Fang Yang, Zheng-Lin Yang, Hou-Bin Zhang. 2021: Inhibition of mTOR signaling by rapamycin protects photoreceptors from degeneration in rd1 mice. Zoological Research, 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. 2021: Inhibition of mTOR signaling by rapamycin protects photoreceptors from degeneration in rd1 mice. Zoological Research, 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

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

  • 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。

     

    Abstract: Retinitis pigmentosa (RP) is an inherited retinal degenerative disease that begins with defective rod photoreceptor function, followed by impaired cone function, and complete blindness in its late stage. To date, however, there is no effective treatment for RP. By carrying a nonsense mutation in the Pde6b gene, rd1 mice display elevated cGMP in conjunction with higher intracellular Ca2+ in their rod photoreceptors, resulting in fast retinal degeneration. Ca2+ has been linked to activation of the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway integrates extracellular and intracellular signals to sense the supply of nutrients and plays a central role in regulating protein and lipid synthesis as well as apoptosis and autophagy. In the present study, we showed that mTOR and phosphorylated mTOR (p-mTOR, activated form of mTOR) are up-regulated in rd1 photoreceptors at postnatal day 10 (P10), a pre-degenerative stage. Moreover, the downstream effectors of mTOR, such as pS6K and S6K, are also increased, suggesting activation of the mTOR signaling pathway. Intravitreal administration of rapamycin, a negative regulator of mTOR, inhibits the mTOR pathway in rd1 photoreceptors. Consequently, the progression of retinal degeneration is slower and retinal function is enhanced, possibly mediated by activation of autophagy in the photoreceptors. Taken together, these results highlight rapamycin as a potential therapeutic avenue for retinal degeneration.

     

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