CYP51A1调控ERS-UPR信号通路维持晶状体内蛋白质稳态的分子机制

白内障是全球首位致盲眼病。研究组发现羊毛甾醇14α-去甲基化酶(CYP51A1)作为白内障致病基因，错义突变CYP51A1-R277C导致先天性白内障，但分子机理未有报道。CYP51A1能够调控其底物羊毛甾醇代谢水平，羊毛甾醇可有效逆转晶状体内蛋白质异常聚集。亚细胞定位显示CYP51A1在内质网富集，内质网应激-未折叠蛋白应答(ERS-UPR)是维持机体内蛋白质稳态的关键调控因子。我们推测：CYP51A1调控ERS-UPR信号通路维持晶状体内蛋白质稳态。晶状体内蛋白质稳态调控机制是阐述白内障致病机理的关键科学问题。本项目拟构建CYP51A1遗传突变模型，证实CYP51A1为白内障致病基因。进一步结合临床样本，探究CYP51A1协同调控ERS-UPR信号通路维持晶状体内蛋白质稳态的代谢网络，系统阐述CYP51A1在晶状体内生理功能及其导致白内障的分子机理，为白内障防治药物研发奠定理论基础。

Cataract is one of the most common visual impairment disease worldwide, especially in developing countries. Presently, the only available therapeutic approach for cataracts is surgical treatment. Our research group has been working on the pathogenesis and prevention strategies of cataract for decades. We have identified CYP51A1 (Cytochrome P450-14DM) is a cataract-causal gene in previous studies. The missense mutation CYP51A1-R277C causes congenital cataract, however the molecular mechanism has not been reported. The substrate of CYP51A1, lanosterol, plays a key role in the prevention of protein aggregation in the lens. We also found that CYP51A1 was enriched in the endoplasmic reticulum, and the endoplasmic reticulum stress-unfolded protein response (ERS-UPR) is a key regulator of cellular protein homeostasis. So, we propose a hypothesis that CYP51A1 might maintain protein homeostasis in the lens by co-regulating the ERS-UPR signaling pathway. How do lens cells maintain normal metabolism and protein homeostasis to keep the transparency of ocular lens? It is an important question to elaborate the pathogenesis of cataract. Research objective of our project is to construct systematic CYP51A1 mutation models and confirm that CYP51A1 is a cataract-causing gene. We will also make full use of clinical cataract samples and cataract models caused by CYP51A1 mutation, from the protein, cellular and animal model levels, to explore the metabolic network that CYP51A1 maintains protein homeostasis in the lens by co-regulating the ERS-UPR signal pathway, to explain the physiological function of CYP51A1 in the lens and the molecular mechanism leading to cataracts. Our project might provide new strategies for the precise prevention and treatment of cataracts.