The roles of beta-catenin, APC and the Wnt/beta-catenin pathway in lens development and cataract

白内障是导致失明的主要原因。许多危险因素已被确定，但导致白内障的基本细胞和分子机制尚不清楚。研究这些机制对于确定未来治疗阻止或预防白内障形成的潜在靶点至关重要。晶状体由上皮细胞和纤维细胞组成。我们的大部分研究都集中在识别调节上皮细胞形成纤维细胞的基因和细胞信号通路上。然而，对调节上皮本身形成的因素所知甚少。由于上皮细胞在某些类型的白内障中受到影响，因此了解控制这些细胞形成和维持的机制至关重要。我们之前的研究已经确定了一个生长因子家族（tgf - β）导致上皮性白内障。重要的是，我们最近的研究已经确定了另一种生长因子信号通路（wnt - β -连环蛋白）对晶体上皮的形成和维持至关重要。我们假设这一途径在白内障形成过程中被破坏。该项目使用最先进的工具和技术来研究Wnt通路的两个中心分子成分（APC和β -连环蛋白）在发育晶状体中的作用。通过基因调控小鼠晶状体中这些蛋白的活性，我们将研究这些分子和Wnt信号通路在晶状体发育中的作用，以及不适当的活性是否会导致异常发育或白内障。我们还将能够研究调节这一途径是否会通过tgf β影响上皮性白内障的形成。该结果将提供这些分子如何调节晶状体结构和功能的详细信息，并有可能确定预防或改善白内障的靶点。

Cataract is a leading cause of blindness. Many risk factors have been identified but the basic cellular and molecular mechanisms that cause cataract are not well understood. Investigation of these mechanisms is essential to identify potential targets for future therapies to arrest or prevent cataract formation. The lens is composed of epithelial and fibre cells. Much of our research has focussed on identifying genes and cell signalling pathways that regulate formation of fibre cells from the epithelial cells. However, considerably less is known about factors that regulate formation of the epithelium itself. As the epithelial cells are affected in some types of cataract it is vitally important to understand the mechanisms that control formation and maintenance of these cells. Our previous studies have identified a growth factor family (TGF-beta) that causes epithelial cataracts. Importantly, our recent studies have identified another growth factor signalling pathway (Wnt-beta-catenin) as being essential for the formation and maintenance of the lens epithelium. We hypothesise that this pathway is disrupted dring cataract formation. This project uses state of the art tools and techniques to investigate the role of two central molecular components of this Wnt pathway (APC and beta-catenin) in the developing lens. By genetically manipulating the activity of these proteins in the mouse lens we will investigate the roles these molecules and the Wnt signalling pathway play in lens development and whether inappropriate activity results in abnormal development or cataract. We will also be able to investigate whether modulating this pathway affects the formation of epithelial cataracts by TGFbeta. The results will provide detailed information on how these molecules regulate lens structure and function and have the potential to identify targets for preventing or ameliorating cataracts.