筛选治疗老年性黄斑变性的小分子化合物

Age-related macular degeneration (AMD) is the most devastating ocular neurodegenerative disorder that accounts for approximately 50% of all blindness cases in the developed countries. Intravitreal injection of vascular endothelial growth factor (VEGF) blocking antibodies is the current medical standard of care for AMD patients. However, less than 50% of patients improve visual acuity after anti-VEGF therapy. The high proportion of non-responders and prevalence of tachyphylaxis suggests that alternative medical treatment for AMD therapy should be urgently explored. The goal of this proposal is to identify novel candidate treatments for AMD. We will use a novel small molecule screening system utilizing real-time cellular analysis to discover compounds that can stabilize retinal vascular barrier function and can be used for AMD therapy in the future. Our screening platform consists of two individual screening assays: the first assay utilizes electric cell substrate impedance sensing to detect changes in endothelial barrier function; the secondary assay, which we use as orthogonal secondary screen, is a direct paracellular permeability assay using a transwell system. For the compound identified using these screens, structure-activity relationship (SAR) will be studied. We will further screen the top candidate compounds in two mouse models of human retinal vasculature disease: VEGF induced retinal permeability and laser induced choroidal neovascularization. The preliminary mechanism of the best compound will be studied using cell and molecular biotechnology.

老年性黄斑变性（AMD）是最具有破坏性的神经性功能紊乱疾病，有一半失明和视力残疾是由AMD导致的。血管内皮生长因子（VEGF）抗体是使用较多的AMD治疗药物，但是仅有不到50%的患者通过VEGF抗体治疗可以缓解病情或提高视力。众多VEGF抗体无疗效患者，及多发的快速抗药反应，表明新AMD药物的急需性。本课题的目标是通过筛选国家化合物样品库的化合物，发现增强视网膜血管稳定性，以用于AMD治疗的小分子化合物。本筛选包括两级：初级筛选拟采用实时细胞分析仪检测细胞单层通透性改变；二级筛选是检测细胞单层通透性的Transwell系统。并将对筛选到的阳性化合物进行结构和活性相关性研究，为化合物的结构优化和改造打下基础。通过动物体内实验，确定化合物对AMD等视网膜血管疾病的疗效。并对活性最高的化合物进行分子机制研究，初步确定其增强血管稳定性的作用机理和作用靶点。