核心蛋白多糖抑制湿性年龄相关性黄斑变性的作用及机制研究

Wet age-related macular degeneration (AMD) that can cause the older blindness affects their quality of life seriously.The supernormal level of Vascular endothelial growth factor (VEGF)secreted by retinal pigmented epithelium (RPE)is the main cause. Decorin can suppress the level of VEGF secreted by tumor cells，however，whether it could play the same role in RPE has not been reported so far. Our preliminary experiment results suggest that : Decorin can inhibit RPE secreting VEGF under hypoxia and the Rac-1 expression, but its molecular mechanism is not clear. So we propose the hypothesis: Decorin may affect secretion of VEGF in RPE by inhibiting the Met-Rac1 signal pathway. To test this hypothesis, we use human RPE, RF/6A cells, mouse model of choroidal neovascularization, cell specific hypoxia-regulated Adeno-associated Virus vector-transfection, siRNA interference and other means from the molecular, cellular, and animal mode aspects to elucidate the role of decorin in supressing the development of wet AMD, through the Met-Rac1 signal pathway. This study provide completely new perspection in treatment of wet AMD .

湿性年龄相关性黄斑变性（AMD）是常见的老年性致盲眼病。视网膜色素上皮细胞（RPE）缺氧导致血管内皮生长因子（VEGF）分泌增多是其致病因素之一。核心蛋白多糖（decorin）可与细胞表面多种受体结合，但能否对RPE分泌VEGF进行调控尚无明确报道。我们预实验结果提示：Decorin能下调RPE缺氧时VEGF的分泌及Rac-1表达，但其分子机制尚不清楚。我们提出假说：Decorin可能通过Met-Rac1信号通路影响RPE分泌VEGF，利用仅在低氧时启动Deocrin基因表达的腺相关病毒载体转染PRE可抑制湿性AMD病变的发生。为验证这一假说，我们构建靶向低氧调控性腺相关病毒载体、利用siRNA技术作用于PRE细胞、小鼠脉络膜新生血管模型，研究decorin抑制湿性AMD的作用，明确Decorin是否通过Met-Rac1途径抑制VEGF分泌的分子机制，为湿性AMD的防治提供新思路。

核心蛋白多糖（decorin）可与细胞表面多种受体结合，但能否对RPE分泌VEGF 进行调控尚无明确报道，在新生血管性视网膜病变中的作用亦无报道。本课题通过siRNA干扰，慢病毒载体等技术转染RPE 细胞，揭示了decorin抑制RPE细胞低氧条件下分泌VEGF的分子通路，并抑制RPE细胞屏障损伤的机制；构建自身互补型腺相关病毒载体，decorin病毒抑制OIR小鼠视网膜新生血管的生成，decorin病毒抑制STZ糖尿病大鼠视网膜新生血管的形成，本课题从分子，细胞和动物水平多方面探讨decorin在早期抑制新生血管性视网膜病变中发挥重要作用，为早期防治缺血性、新生血管性视网膜疾病提供新的思路。