Wnt/β- catenin信号通路在后发性白内障形成中的作用

Posterior capsule opacification (PCO) is the most common complication leading to loss of vision after cataract surgery. Both the posterior capsule wrinkling associated with PCO and the treatment for PCO with Nd:YAG laser posterior capsulotomy could cause the tilt and dislocation of intraocular lens (IOL), which is able to impede the optical function of premium IOL. Therefore, research on the pathogenesis of PCO is crucial for the prevention and treatment of PCO..Recently, we have discovered that moderate oxidation could modulate LECs adaptation provoke a shift towards a fibrotic state via a Wnt/β-catenin dependent signaling pathway mediated EMT pathogenesis. These studies extend our hypothesis that the chronic oxidative stressed microenvironment induces LECs adaptation/transformation via a Wnt/β-catenin mediated EMT pathway. However, it is still unclear when Wnt/β-catenin signaling is activated and whether there is a cross talk between Wnt/β-catenin and TGFβ signaling during the phases of development of PCO. .In the present study project, we plan to clarify the role of Wnt/β-catenin signaling on transdifferentiation of LECs under the condition of chronic oxidation into mesenchymal cells, and especially the link between Wnt/β-catenin and TGFβ signaling pathway during the phases of development of PCO using the model of human lens epithelial (HLE-B3) cells line, lens explants experimental models from the Gclc or Gclm knockout mice, and a rabbit model with the similar eye size to human which has the lens phacoemulsification and intraocular lens implantation. The purpose of the present study project is to clear the molecular mechanism of pathogenesis involved the development PCO, providing the evidence for the medication therapy targeted the identified molecular and material research of IOL.

后发性白内障(PCO)是导致白内障患者术后视力下降最常见的并发症，其伴随的晶状体囊袋收缩和常规激光晶状体后囊膜切开治疗致人工晶状体(IOL)的倾斜和偏位，均导致多焦等功能性IOL光学功能不能正常发挥作用，严重影响术后远期患者视觉质量。故研究PCO的发病机制和防治意义重大。我们近期研究发现Wnt/β-catenin信号通路的激活致人晶状体上皮细胞(LEC)纤维化，是PCO形成中除TGFβ之外的新通路。本课题拟从人LEC细胞系、晶状体囊袋培养和兔晶状体摘除植入IOL模型层面，确定Wnt/β-catenin信号通路在慢性氧化损伤诱导LEC修复和转化为纤维细胞过程不同时相的具体作用，探讨Wnt/β-catenin信号通路与经典的TGFβ信号通路在PCO形成过程中是否存在交互作用机制，旨在阐明PCO形成过程中不同时相的关键分子通路和机制，为后续防治PCO的药物和材料学研究提供分子治疗靶点和依据。

后发性白内障(PCO)是白内障患者术后视力下降最常见的并发症。研究发现白内障术后慢性氧化应激刺激下，经典TGFβ信号介导晶状体上皮细胞（LEC）间质转分化（EMT），调控PCO的发生。我们近期合作研究发现Wnt/β-catenin信号通路是PCO形成中除TGFβ之外的新通路，但具体机制尚不明确。因此，探究经典Wnt信号通路在慢性氧化损伤诱导的LEC的EMT过程不同时相的具体作用，及其与经典TGFβ信号通路是否存在交互作用机制是本项目的研究重点。.研究内容：构建小鼠模拟白内障手术模型、猪晶状体上皮细胞氧化应激模型和兔眼后发性白内障模型，观察组织形态学改变、检测EMT指标及信号通路表达等，通过体内和体外实验分析PCO发生的病理改变及分子通路变化及机制。.研究结果：1.在小鼠PCO形成过程中，经典TGF-β/Smad和Wnt/β-catenin信号通路均被激活，且TGFβ信号先增高后降低，而Wnt信号表达持续增强；2.适度内/外源性氧化剂可以诱导LECs发生氧化应激，且经典TGF-β和Wnt信号均被激活；3.单独抑制TGFβ或Wnt信号仅部分阻断LEC的EMT，同时抑制两条通路则基本完全阻断EMT；4.在兔眼后发性白内障模型中发现TGFβ信号主要在术后早期激活，经典Wnt信号随术后时间延长而表达增加。.科学意义：1.明确了Wnt/β-catenin信号通路在LEC的EMT及PCO形成中的调控作用；2.证实了经典Wnt通路与TGFβ通路在PCO形成过程中存在时空特异的协同作用机制；3.初步阐明PCO形成过程中不同时相的关键分子通路和机制，为后续防治PCO的药物和材料学研究提供新的分子治疗靶点和策略。