琥珀酸盐及其受体GPR91介导的信号通路调控快速视网膜变性小鼠视网膜新生血管生成的机制研究

视网膜新生血管是一种常见的致盲性病变，寻找预防和治疗视网膜新生血管性疾病的新方法显得尤为重要。有研究认为视网膜感光细胞变性会阻断视网膜新生血管的形成，也有报道提示同一个体可共同发生这两种疾病。我们前期研究发现快速视网膜变性小鼠在高氧条件下可以诱发出视网膜新生血管，然而其严重程度低于野生型小鼠，视网膜组织VEGF的表达水平也相应地降低。由于快速视网膜变性小鼠感光细胞早期大量凋亡，而感光细胞尤其是视杆细胞耗氧量巨大，因而其视网膜组织局部耗氧量下降，产生视网膜组织的一个相对“高氧”的状态，此时有氧代谢加快，我们设想此时三羧酸循环的中间代谢产物琥珀酸盐的释放也会减少，从而也减少了与GPR91的结合和信号转导，进一步减少新生血管的发生。本项目拟通过离体和在体两方面来研究琥珀酸盐和GPR91信号通路在快速视网膜变性小鼠视网膜新生血管生成中的影响作用，以及与PEDF的相互作用及其对视网膜新生血管的影响。

Retinal neovascularization is a common cause of blindness. Identifying new methods of preventing and treating retinal angiogenic diseases is extremely important. Previous reports had stated that the retinal photoreceptor cell degeneration might inhibit the development of retinal angiogenesis and neovascularization, however, there were still reports found that the retinal neovascularization occurred in patients with retinitis pigmentosa and in retinal degeneration mouse model. In the previous study, we adopted the albino and colored inbred mouse strain with retinal photoreceptor cells degeneration to investigate the relationship between retinal neovascularization and retinal photoreceptor cells degeneration. Our results suggest the loss of photoreceptor cells can not totally obstruct the retinal neovascularization in the rapid retinal degeneration mouse model. The vascular endothelial growth factor (VEGF) expression level was lower in the retinal degeneration mice. Due to the loss of large number of photoreceptor cells in rapid retinal degeneration mice, and the oxygen consumption of photoreceptor cells is huge. As a result, the local oxygen consumption of the retinal tissue decreases, resulting in a relatively "hyperoxic" state of the retinal tissue. At this time, aerobic metabolism is accelerated, and the release of the intermediate product of the succinate of the tricarboxylic acid cycle is also reduced, which also reduces the combination with GPR91 and signal transduction，and then reduce the occurrence of neovascularization. To further explore the mechanism of inhibiting effect of retinal photoreceptor cell degeneration to retinal neovascularization. This project intends to study the effects of succinate and GPR91 signaling pathway on retinal neovascularization in mice with rapid retinal degeneration, as well as interaction with PEDF and effects on retinal neovascularization in vitro and in vivo.