蛋白质SUMO化调节晶状体发育和白内障形成的分子机制

蛋白质SUMO化是真核生物中重要的调控机制。在眼睛发育过程中，蛋白质SUMO化对晶状体和视网膜的分化起着关键作用。 我们前期的工作表明，SUMO化通过调节转录因子Pax-6和Sp-1的功能，控制晶状体发育。SUMO1失活导致晶状体易受应激因子诱导而产生细胞凋亡，形成白内障。SUMO化是否调节其他转录因子来控制晶状体发育及如何调节白内障的发生则有待进一步研究。本项目将应用现代分子细胞生物学方法来深入探讨SUMO化在晶状体发育和白内障形成中的功能及其分子机制，以确定1）SUMO化如何调节转录因子HSF4和p53的功能来调控晶状体发育；2）改变靶分子的SUMO化状态如何调节白内障的发生; 3）敲除SUMO1如何导致晶状体丧失抵抗应激因子的能力，产生凋亡，形成白内障。这些结果为进一步了解晶状体发育的分子机制和白内障形成的病理机制带来崭新信息，并为白内障的治疗提供新的切入点。

Sumoylation is an important regulatory mechanism in Eukaryotes, During eye development, sumoylation of different transcription factors becomes an indispensable mechanism for normal differentiation of both lens and retina. Our previous studies have shown that sumoylation regulates transcription factors Pax-6 and Sp-1 to promote lens development. SUMO1 knockout leads to hyper-sensitivity of the ocular lens to stress-induced apoptosis, followed by cataractogenesis. We hypothesize that sumoylation can regulate additional transcription factors to promote lens differentiation, and also regulate the sumoylation status of the target molecules to control cataractogenesis. To validate this hypothesis, we proposes to utilize modern molecular and cellular biology methodology to conduct comprehensive analyses of sumoylation control of both lens differentiation and cataractogenesis, and intend to determine 1) if sumoylation can modulate the functions of HSF4 and p53 to exert control of lens development; 2) how SUMO-conjugation modulates the sumoylation status of the target molecules to regulate cataractogenesis; 3) why SUMO1 loss causes rapid apoptosis followed by cataractogenesis when UVA irradiation or oxidative stress is imposed to the SUMO1 knockout mouse lenses. The obtained result will broad our understanding of the molecular mechanisms governing lens development, and also provide novel information for the improvement of cataract treatment.