VASH2催化α-tubulin去酪氨酸化在脉络膜新生血管中的作用及机制研究

湿性年龄相关性黄斑变性（wet-AMD）是导致视力损害的重要疾病，脉络膜新生血管（CNV）是其最重要的病理基础。本项目前期发现wet-AMD治疗不应答患者房水中血管生成调控因子VASH2高表达，体外预试验初步证实VASH2不依赖于VEGF，高表达于眼底新生血管，具有促进细胞自噬和视网膜血管内皮细胞管型形成的潜能；既往研究提示VASH2可催化α-tubulin去酪氨酸化，而α-tubulin去酪氨酸化与细胞自噬相关。据此我们提出假说：VASH2催化α-tubulin去酪氨酸化，并通过细胞自噬促进CNV病理发生。围绕该假说，本项目拟探讨VASH2催化α-tubulin去酪氨酸化在CNV中的发病机制。研究结果将为深入解析CNV的病理机制及开发新的靶向治疗手段提供新的思路与实验基础。

Wet age-related macular degeneration (wet-AMD), characterized by choroid neovascularization (CNV), is one of the leading causes of irreversible visual impairment. Our previous work suggests the high expression of VASH2 in aqueous humor in wet-AMD patients with poor response to anti-VEGF treatment. Further in-vitro experiments have demonstrated the pro-autophagic and pro-angiogenic capability of VASH2 as a new cytokine in fundus neovascularization. Recently, VASH2 has been reported to catalyze α-tubulin detyrosination, which is related to cell autophagy. Taken together we assume that VASH2 induces autophagy-mediated CNV by catalyzing α-tubulin detyrosination. This proposal is to explicate the role of α-tubulin detyrosination and cell autophagy underlying the mechanism of VASH2-induced CNV. This work could reveal the mechanism of VASH2 in CNV pathogenesis and provide a novel target for future treatment of wet-AMD.