Smad4介导的信号转导通路网络在眼发育中的作用

The developmental mechanism of congenital cataract is one of the highlights in the pathogenesis research. In the prophase work ,the applicant has found that the Smad4 gene knockout mice conditional expression lackness can lead to the lens and retinal dysplasia, that is the congenital cataract. Smad4 , as a member of the BMP signaling pathway, has very important role in transcriptional regulation,and it can directly or indirectly influence the expression of multiple signal transduction pathways. This project starts from the regulatory mechanism of the lens, the retina development and the induction process between the organizations. After conditional knockout Smad4 in lens and retina, we focus on the abnormal expression of Wnt, Notch, and RA critial factors in their signaling pathways, because of the cross linking fuctions between them. Study in vivo and in vitro the regulatory relationship of Smad4, Wnt, Notch and RA pathways from the representation to the research of molecular mechanism by using in situ molecular hybridization, immunofluorescence combined with different Smad4 conditional knockout mice model. Further clarify Smad4 and the BMP signaling pathways play vital role in the lens, retina induction and development. It also provides the theory basis of the pathogenesis of congenital cataract and realization of prenatal diagnosis and gene therapy.

先天性白内障的发育学发生机制是目前的研究热点之一。申请人前期工作中利用Smad4基因敲除小鼠发现Smad4条件敲除可导致晶状体视网膜发育异常，出现先天性白内障等。Smad4作为BMP信号通路中的一员有重要的转录调控作用，它可以直接或间接影响多个信号转导通路的表达。本项目从晶状体、视网膜发育及发育过程中的组织间诱导的调控机制入手，以研究Smad4在晶状体及视网膜条件敲除后致与其功能交叉的Wnt、Notch和RA信号通路关键因子改变的分子机制为核心，通过原位分子杂交、免疫荧光等实验结合Smad4 LeCre及SixCre条件敲除小鼠模型，在体及离体对Smad4与Wnt、Notch及RA信号通路之间的调控关系进行从表征到分子机理的研究。进一步阐明Smad4及其所在的BMP信号通路在晶状体、视网膜的诱导和发育过程中所发挥的重要作用，为明确先天性白内障等发育性眼病的发病机制，实现产前诊断和基因治疗。

先天性白内障的发育学发生机制是目前的研究热点之一。本项目从晶状体、视网膜发育及发育过程中的组织间诱导的调控机制入手，以研究Smad4在晶状体及视网膜条件敲除后致与其功能交叉的Wnt等信号通路关键因子改变的分子机制为核心，发现Smad4基因表面外胚层敲除后，出现不同程度的小眼畸形和严重的先天性白内障，晶状体可能通过释放某种信号调控视网膜上的Hh和Wnt信号通路影响视网膜的发育，引起视网膜皱褶、视网膜脱离以及视网膜厚度变化，同时也发现结膜杯状细胞发育延迟，数量明显减少，阐明了Smad4及其所在的信号通路在晶状体、视网膜的诱导和发育过程中所发挥的重要作用，为明确先天性白内障等发育性眼病的发病机制，实现产前诊断和基因治疗提供理论依据。