申请人前期研究已发现20多个可致先天性白内障（先白）的基因突变。为了进一步寻找先白的新基因新突变，探索可能的病理机制，申请人从蛋白基因组学的角度，利用病人特异性白内障疾病模型即利用申请人近期创立的“荷包蛋”法将病人尿液细胞来源的iPSCs体外诱导成与病人晶状体类似的混浊再生晶状体，结合全基因组测序、蛋白质谱分析、siRNA干扰、CRISPR-CAS9技术、质粒转染等，并结合细胞模型在基因组学、蛋白组学两个层面从全新的视角探寻未知突变家系的新基因新突变并研究其分子机制。本课题采用的病人特异性白内障疾病模型不仅保留了病人特异性的遗传背景，而且还模拟了白内障发病进程，为本课题的实施提供了可能性。研究成果将为先白突变基因修复、再生晶体及干细胞治疗提供理论基础。

More than 20 mutations related to congenital cataracts have been found and reported by our group over the past decade. To further explore the novel genes and novel mutations causing congenital cataracts, proteogenomics of patient-specific regenerated lens was introduced into our project. Urinary derived induced pluripotent stem cells (iPSCs) from the patients were first differentiated into regenerated lens which showed similar characteristics to patient opacity lens using our newly developed “fried egg” method. Molecular mechanisms were then explored using techniques such as whole genome sequencing, protein mass spectrometry, iTRAQ, siRNA assay, CRISPR-CAS9, transfection and et al, as well as some cellular cataract models. The patient-specific cataract model generated in this project not only retained the patient’s genetic background, but also mimicked the cataract progression, therefore, played a vital role in our study. Exploration may lead to clinical opportunities for gene repair and stem cells therapy in congenital cataracts.