以晶状体蛋白聚集体为靶点筛选白内障治疗药物及作用机制研究

Cataract, opacification of the lens, is one of the commonest causes of loss of useful vision, with an estimated 95 million people worldwide affected. Since cataract is primarily an age-related disorder, the worldwide burden of blindness is increasing as a result of both growth and ageing of the population. However, Cataract surgery remains one of the most cost-effective treatments and the most commonly used procedure in many countries. Many people in the developing world become blind due to cataracts because of a lack of medical resources. A new drug treatment for cataracts based on eye drops would remove this obstacle, as current agents and dietary recommendations are generally ineffective. There are two key barriers to cataracts drug development: without proper drug targets and the only evaluation criteria of cataracts medication effect can not be applied to high-throughput screening of drugs. Our previous work showed that lanosterol reverses protein aggregation in cataracts, it may substantially boost the cataract pharmacopoeia. This project intends to choose the aggregates of misfolded crystallin as the drug target, and to establish a set of methods for high throughput screening cataract treatment compounds. The drug targets used in this project for screening include the aggregates formed by misfolding proteins in lens epithelial cells, turbid lens samples from cataract patients, cataract lentiod bodies induced by iPSCs and cataract animal models. What’s more, we will establish a set of lanosterol derivative compound library and a plant-sourced compounds library, and then screen the cataract drugs through the screening system. We are aiming to screen 2-3 kinds of active small molecule compounds as preclinical candidates for cataracts treatment, and to elucidate the molecular mechanism of lanosterol reversing protein aggregation in cataracts.

白内障疾病是全球致盲率最高的眼科疾病，随着全球老龄化的加剧，白内障的发病率越来越高。目前，有效治疗白内障的方案仍是手术治疗，无有效药物治愈白内障。阻碍白内障疾病药物研发的关键问题是：没有确定合适的药物靶点和药效评估标准的局限，无法进行高通量的药物筛选。前期研究发现，羊毛甾醇可以有效逆转白内障疾病聚集体，让人们看到了白内障药物治疗的希望。本项目拟选择晶状体内蛋白质错误折叠形成的聚集体为靶标，分别采用细胞内蛋白质错误折叠形成的聚集体、白内障患者手术摘除的混浊晶体、iPSCs诱导分化的白内障晶体、白内障动物模型四个不同层次的聚集体模型，通过生物物理学、生物化学与分子生物学建立一套完善的白内障防治药物筛选评估系统。同时，建立羊毛甾醇衍生化合物库和天然植物小分子化合物库，通过药物筛选评估系统，高通量筛选白内障疾病的防治药物并进行临床前候选药物的研发。

白内障疾病是全球致盲率最高的眼科疾病，随着全球老龄化的加剧，白内障的发病率越来越高。目前，有效治疗白内障的方案仍是手术治疗，无有效药物治愈白内障。阻碍白内障疾病药物研发的关键问题是：没有确定合适的药物靶点和药效评估标准的局限，无法进行高通量的药物筛选。我们利用细胞内蛋白质错误折叠形成的聚集体、白内障患者手术摘除的混浊晶体、iPSCs诱导分化的白内障晶体、白内障动物模型四个不同层次的聚集体模型。我们发现了1）白内障致病新基因突变或新突变位点，系统阐明不同类型白内障发病机制，为精准治疗提供理论依据。2）以白内障术中混浊晶状体碎屑样本建立了药物验证评估系统。3）构建了先天性白内障小鼠模型和年龄相关性家兔模型，从不同角度阐述了除晶体蛋白稳态外，还有其他通路参与白内障的发生发展。4）系统解析了羊毛甾醇在聚集体调控方面的关键功能因子及相应的分子机理。5）从天然植物小分子化合物库中筛选到了靶向作用于晶状体蛋白的小分子并探索其治疗白内障的机制。