PI3K/Akt信号通路介导自噬调控巩膜胶原降解参与近视发生发展的作用机制研究

There is a continued increase in the prevalence of myopia and thus myopia has become a significant public health concern. However, the exact mechanism of myopic development and progression has not been fully clarified. The previous studies have showed the synthesis and the degradation of the scleral collagen is critical in the myopic development. Autophagy is a fundamental cellular homeostatic process that cell use to degrade and recycle cellular proteins and remove damaged organelles with the actions of lysosome. Previous studies showed the autophagy can promote the degradation of the collagen. We have found an increase in autophagy in the sclera of form-deprived guinea pigs and a decrease in that of recovery eyes. Thus we hypothesize that the activation of the autophagy is critical for the myopic development, which has not been reported so far. Accordingly, we will explore the new mechanism that how autophagy promotes degradation of collagen through PI3K/Akt signaling in myopic development with genetic transfection, RNA interference, western blot, and ocular biometric parameters measurements. Taken together, we expect to uncover the role of the autophagy in the normal visual and myopic development. It may provide a promising therapeutic strategy for preventing and/or treating myopia.

近视发病率逐年升高，已成为一个严重的公共卫生问题，但其发生发展机理仍不清楚。研究证实巩膜胶原的合成和降解是近视形成的关键环节之一。自噬是是一种溶酶体依赖性的细胞内多余大分子物质和受损细胞器降解的过程，生命体借此维持蛋白代谢平衡及细胞环境稳定。研究报道自噬能够促进多种细胞的胶原降解，而我们前期研究发现形觉剥夺性近视豚鼠的巩膜内自噬水平明显增加，近视恢复期则明显降低。因此，申请者提出自噬通过调控巩膜胶原的降解参与近视的形成，目前尚无相关报道。针对上述假说，本项目拟通过基因转染、免疫印迹、透射电镜和眼球生物学参数检测等生物学方法，通过体内和体外实验，深入探讨自噬如何通过PI3K/Akt信号通路调控胶原降解参与近视的发生发展，从而阐明自噬在视觉发育及近视发生发展过程中的作用及其机制，为近视机制的研究提供新思路，为近视的防治提供新靶点。

近年来近视发病率逐年升高，已成为一个严重的公共卫生问题，但其发生发展机理仍不清楚。鉴于巩膜胶原的合成和降解是近视形成的关键环节之一，而以往的研究报道自噬能够促进多种细胞的胶原降解。此外，我们前期研究发现形觉剥夺性近视豚鼠的巩膜内自噬水平明显增加，近视恢复期则明显降低。因此，申请者提出自噬通过调控巩膜胶原的降解参与近视形成的假说。在基金资助阶段，申请者完成了基金申请书中的主要研究计划，阐明了自噬参与了近视发生发展的过程，病重点讨论了自噬调控胶原代谢过程的具体分子机制。目前研究结果主要包括：1. 巩膜自噬水平的变化是否参与了近视的发生发展；2.自噬通过调控巩膜胶原的降解参与近视的发生发展；3.巩膜内自噬活性的增强能够通过PI3K/Akt信号通路促进巩膜胶原的降解从而导致近视的发生发展。截止目前在基金资助下，申请者已发表SCI论文3篇。