PGF突变介导的周细胞与内皮细胞crosstalk在湿性年龄相关性黄斑变性中的作用及机制研究

湿性年龄相关性黄斑变性（wAMD）是老年人不可逆失明的主要原因，抗VEGF治疗的新靶点-胎盘生长因子（PGF）在血管生成中发挥重要作用。我们研究发现PGF是wAMD的新易感基因，PGF c.-475_-458del突变可增加PGF转录活性并提高wAMD发病风险，但其在wAMD中的作用尚未明确。为此，本项目拟通过CRISPR/Cas9技术，明确PGF突变在wAMD中周细胞与内皮细胞crosstalk发展密切相关的分子改变（视网膜炎症标志物）和病理改变（毛细血管退变及血管渗漏）中的作用，体外细胞实验研究PGF突变是否通过其蛋白水解酶的活性影响抗凋亡蛋白，或激活p38 MAPK信号通路增加细胞串扰衍生炎症因子，进而理解PGF突变介导的周细胞与内皮细胞crosstalk在wAMD发展过程中的分子机制，为wAMD的遗传结构及发病机理提供新的见解。

Wet age-related macular degeneration (wAMD) is a leading cause of irreversible blindness among the elderly. The placental growth factor (PGF), a new target for anti-VEGF treatment, plays an important role in angiogenesis. A novel variant c.-475_-458del in PGF increases the transcriptional activity and the risk of wAMD. However, the role of PGF in wAMD remains unknown. Therefore, this project tends to clarify the molecular changes (retinal inflammatory markers) and pathological changes (capillary degeneration and vascular leakage) that are closely related to the development of pericyte-endothelial cell crosstalk by PGF mutation in wAMD by using CRISPR/Cas9 technology. In addition, the project will investigate whether PGF mutation affects anti-apoptotic proteins through their proteolytic enzyme activity or activate p38 MAPK signaling pathway in vitro. Understanding the role of pericyte-endothelial cell crosstalk by PGF mutation in wAMD could provide new insights into the genetic structure and pathogenesis of wAMD.