去磷酸化对P53功能和晶状体分化的调节研究

白内障是全球首要致盲眼病，其发病机制并不明了。已有研究表明p53参与眼睛晶状体发育和成年白内障形成的调控，p53正常功能对维持晶状体透明结构至关重要。磷酸化修饰是p53活性调节的重要途径。在已经发现的17个p53的磷酸化位点中，我们的前期工作已经表明p53在Ser-6,9和20位点的去磷酸化修饰直接影响p53的转录活性和晶状体的分化。p53对晶状体发育关键转录因子c-Maf 和Prox-1，及和分化相关的基因αA、βA3/A1和γA-crystallin有着非常重要的调控作用。本课题将使用分子细胞生物学的方法以确定：1）p53在其它位点的去磷酸化对其功能和晶状体发育的调节作用，和2）p53在小鼠眼睛不同发育时期以及各种不同白内障病人晶状体上皮细胞中的磷酸化状态。其结果将阐明p53去磷酸化对其功能和晶状体分化的调控机制并揭示蛋白质去磷酸化在白内障形成中的潜在作用，为白内障防治提供新的切入点。

Cataract is the leading cause of blindness worldwild, the exact molecular mechanism is not clear. Previous studies have shown that p53 not only can regulate expression of key transcription factors including c-Maf and Prox-1, and differentiation related molecules such as αA、βA3/A1 and γA-crystallin genes during lens development, but also is implicated in the cataractogenesis in adults. The stable activity and function of p53 are important to maintain homeostasis of the transparent lens. Phosphorylation and dephosphorylation are known key post-translation modifications regulating p53 functions. So far, 17 phosphorylation sites have been identified. Our recent studies have shown that dephosphorylation of P53 at ser-6, -9 and -20 sites exert negative controls on expression of c-Maf、Prox-1 and αA-crystallin gene. Here we propose to study 1) how dephosphorylation of p53 at other sites controls p53 function and lens differentiation. 2) the dephosphorylation status of p53 in the developing mouse lens, various types of cataractous lenses from patients. It is expected that the present study will help to determine the dephosphorylation control of p53 functions and lens differentiation, moreover, the possible functions of p53 dephosphorylation in cataractogenesis, thus shedding light to the novel strategies of cataract prevention and treatment.