脉络膜新生血管（CNV）是湿性年龄相关性黄斑变性（wAMD）首要致盲因素，单一靶点抗VEGF治疗仅使有限患者受益。我们前期研究证实，抗VEGF治疗后存在血管重塑，是造成治疗抵抗和视力损伤的病理基础。补体激活导致持续慢性炎症可与周细胞以及巨噬细胞相互作用，与CNV血管渗漏、持续出芽和纤维化相关，据此构建新药VEGF和补体双靶点融合蛋白IBI302治疗wAMD。本项目以补体介导周细胞迁移和巨噬细胞活化作用及机制为切入点，在Collα1-GFP转基因小鼠CNV模型及体外细胞共培养模型中进一步研究药物在CNV重塑不同阶段作用的主要靶细胞及其调控机制；结合已建立SSOCTA无创血管评价技术，观察wAMD患者CNV血管重塑及其在药物干预后的变化，从而明确抗VEGF、抗补体联合治疗的临床效果。为今后开展双靶点甚至多靶点药物临床研究，优化治疗方案，进一步提高患者预后提供理论基础和应用支持。

Choroidal neovascularization (CNV) is the primary cause of blindness in wet age-related macular degeneration (wAMD), and mono-target anti-VEGF therapy could only benefit limited patients. In previous studies, we have proved that vascular remodeling after anti-VEGF is the pathological basis for anti-VEGF treatment resistance and visual impairment in patients with wAMD. Complement activation and chronic inflammation interact with pericytes and macrophages, inducing the vessels exudation, sprout and fibrosis. Thus, bispecific antibody fusion protein of VEGF and complement (IBI302) were produced as a new agent to treat wAMD. In this project, we would focus on the role of complement in pericyte migration and macrophage activation to investigate its main target cells and regulatory mechanisms during different stages of CNV remodeling by Collα1-GFP transgenic CNV model and in vitro cell co-culture. Further we would observe vascular remodeling and its alteration after treatment among the wAMD patients by SSOCTA to define the clinical efficacy of combination therapy. Therefore, this project would provide a solid theoretical foundation and support for dual-target or even multi-target drug clinical research, therapy optimization and prognosis improvement of AMD patients.