人类配对盒基因（Paired Box Gene，简称Pax6）是控制眼睛和大脑发育的关键基因。Pax6缺失导致胚胎发育异常，大脑发育残缺，眼睛和鼻子缺失。由Pax6突变或其它因素造成的表达水平改变导致一系列眼睛疾病: 虹膜缺失、白内障、青光眼及黄斑病变等。因此，对Pax6功能及其调控机制的研究在临床医学上有十分重要的意义。我们最近的研究表明P32 Pax6的激活需要经过类泛素化修饰（Sumoylation, 简称SUMO化）。SUMO化修饰是否能够调节其它Pax6异构体(P48，P46和P43 Pax6)则有待进一步研究。本项目拟用分子细胞生物学的方法来研究SUMO化对上述三种Pax6异构体的表达水平及其功能的调节机制，并探讨其与上述各种眼睛疾病之间的关系，其结果将阐明SUMO化对Pax6表达和功能的调控机理，并进一步帮助了解与Pax6相关疾病的病理机制，为它们的诊断和治疗提供新的切入点。

Pax6 is a master regulator of eye development.It is expressed in the region of anterior surface ectoderm corresponding to the future adenohypophyseal,olfactory and lens placodes,optic vesicle and other parts of the future brain.Pax6 null mice do not form olfactory and lens placodes and show disrupted pituitary gland development.Pax6 mutations and other factors causing altered expression of Pax6 lead to a series of ocular diseases such as absence of iris, cataract, glaucoma,retinoblastoma,and WAGR,etc.Thus,it is extremely important to have a thorough understanding of the functional mechanisms of Pax6 and it's regulation in order to elucidate the mechanisms mediating various ocular diseases.Pax6 is localized at 11p13 of human chromosome 13,and the genomic gene with 25 kb codes for 14 exons.Pax6 protein exists in 4 diffferent isoforms:p48,p46,p43 and p32.While the functions of p46 Pax6 has been extensively studied and investigation of P48 Pax6 function has also been reported,little is known about the functional mechanisms of p32 and p43 Pax6.We have recently shown that activation of p32 Pax6 requires SUMO1-mediated sumoylation.Whether sumoylation regulates expression and functions of other Pax6 isoforms remains to be determined.. Sumoylation,a post-translational modification is a process in which the small ubiquitin-like modifers (SUMOs) are conjugated to target proteins by three ligases.Three SUMO isoforms have been identified.While SUMO2 and SUMO3 share 97% sequence homology,they have significantly difference with SUMO1 (45% sequence difference between SUMO1 and SUMO2/3).. Our recent study reveals that SUMO1 and SUMO2/3 have distinct functions in regulating lens differentiation.While SUOM1 promotes lens differentiation,SUMO2/3 inhibits this process. The underlying mechanism mediating this contrast functions of different SUMOs is derived from their differential regulation of the transcription factor SP-1 and likely other factors.Whether SUMO1 and SUMO2/3 can also differentially control the functions of Pax-6 remains to be studied.. In the present application,we propose to study the sumoylation regulation of Pax6 expression and functions.Using molecular and cellular biology technology,we want to determine:1) what are the sumoylation patterns of different isoforms of Pax6 in the normal ocular tissues and those from patients with various ocular diseases?2) does sumoylation regulate their expression levels?3)what is the function of P43 Pax6?4) does sumoylation regulate the functions of various isoforms of Pax6 in vitro and in vivo?The proposed study will determine how sumoylation controls Pax6 expression and functions.Moreover, this study will help to understand the molecular mechanisms mediating various Pax-6 related ocular diseases,and shed light to their clinic diagnosis and therapeutic treatment.