基于波形蛋白的年龄相关性白内障发病机制研究及相关药物筛选

Age-related cataract is the most common eye disease. Although the surgery may help the patient to gain their vision, it is far from the ideal therapy for human being in long term in the history. Since cataract is not a single disease but a cluster of lens disorders caused by different etilology via various mechanisms, the goal of treating cataracts with topical drugs could only be achieved through the understanding of each type of cataracts. Previously, we found that vimentin (VIM) expression was higher in cortical cataract than in nuclear cataract. Our hypothesis is that SNPs in VIM promoter and epigenetic regulation may be involved in the change of VIM expression. This study will begin with confirmation of the relationship between the changes in VIM and cataract type, and then followed by a case-control study on VIM promoter SNPs. Based on the discovery in the SNPs screening, we will continue our efforts in the mechanistic study. Furthermore, potential anti-cataract molecules will be screened using the small molecule library.

年龄相关性白内障是最常见的致盲眼病。虽然手术能够帮助大多数患者恢复视力，但人类对白内障的认识和治疗方法仍需要进一步提高，最终应达到简单、有效的药物可以停止或延缓白内障发生的目标。各类白内障的发病机制不尽相同，所以有针对性地对每种白内障进行深入研究是白内障药物研究的前提和基础。我们发现，年龄相关性皮质性白内障晶体中的波形蛋白（VIM）显著高于核性白内障，并确定与VIM的转录调控有关，更提示SNP差异和表观遗传机制可能参与在发病机制中。本课题将继续深入研究：明确VIM表达改变与白内障类型的关系，筛选出皮质或核性白内障患者VIM转录调控区可能存在的SNP位点，并进一步确认该位点对VIM转录调控的影响，以阐明该类白内障的发病机制。同时，以VIM的表达为核心指标，采用化合物小分子库进行抗白内障药物筛选，期望找到能干预白内障发生发展的潜在药物。

年龄相关性白内障是最常见的致盲眼病。虽然手术能够帮助大多数患者恢复视力，但人类对白内障的认识和治疗方法仍需要进一步提高，最终应达到简单、有效的药物可以停止或延缓白内障发生的目标。各类白内障的发病机制不尽相同，我们有针对性地对皮质性白内障进行深入研究发现，年龄相关性皮质性白内障晶体中的波形蛋白（VIM）显著高于核性白内障，并确定与VIM 的转录调控有关；发现SNP差异与YY1招募PRC2参与VIM表达调控。同时利用Crispr-Cas9技术构建了药物筛选细胞株，采用化合物小分子库进行抗白内障药物筛选。本项目的完成对皮质性白内障预测提供了一定依据，并对潜在药物进行了初步筛选。