Functional Analysis of Novel Genes in Eye Development and Vision

1：Lengsin是谷氨酰胺合成酶(GS)超家族中的一个新成员，该家族是脊椎动物眼晶状体特有的。Lengsin在终末分化的次级纤维细胞层中特异表达，在该层中，细胞核和其他细胞器丢失，细胞骨架和细胞内连接重新组织。Y2H实验表明，Lengsin作为晶状体主要细胞骨架成分的伴侣，参与了终末分化过程中细胞成分的重组。已经产生了Lengsin的敲除模型，导致了老年性皮质性白内障的发生。Lengsin也是人类ARCC1的候选基因座，目前正在评估中。 3：Retbindin是一种新的视网膜蛋白。我们已经证明了视黄醇结合素本质上是光感受器所特有的，并且人类基因有不同的视锥细胞和视杆细胞启动子。转基因小鼠模型表明，视黄素在控制视网膜中类视黄素和类胡萝卜素水平方面具有作用。 4：AMD和补体因子H(CFH)。CFH的常见序列变异在决定老年性黄斑变性(AMD)的易感性方面起着重要作用。利用老年人RPE/脉络膜和视网膜的酵母双杂交文库和CFH的AMD相关结构域7的诱饵构建物，我们已经确定了人RPE/脉络膜中潜在的CFH结合的重要靶点。这些结果已经通过免疫荧光定位得到证实，并对AMD的进展进行干预具有一定的意义。目前正在开发一种检测方法，以研究可以调节这种结合活性的药物。

1: Lengsin is a novel member of the glutamine synthetase (GS) superfamily that is specific for the vertebrate eye lens. Lengsin is expressed specifically in the layer of terminally differentiating secondary fiber cells in which nuclei and other organelles are lost and cytoskeleton and intracellular junctions are reorganized. Y2H experiments suggest that lengsin has a role as a chaperone of major cytoskeletal components of the lens and participates in the reorganization of cellular components in terminal differentiation.A knock out model of lengsin has been produced which gives rise to age-related cortical cataract. Lengsin is also a candidate locus for ARCC1 in humans and is under evaluation. 3: Retbindin is a novel protein of the retina. We have shown that retbindin is essentially specific for photoreceptors and that the human gene has separate cone and rod cell promoters. A transgenic mouse model shows suggests that retbindin has a role in control of retinoid and carotenoid levels in the retina. 4: AMD and complement factor H (CFH). Common sequence variants of CFH have major roles in determining susceptibility to age-related macular degeneration (AMD). Using yeast 2-hybrid libraries for aged human RPE/choroid and retina and bait constructs for the AMD-related domain 7 of CFH we have identified potentially important targets for CFH binding in human RPE/choroid. These results have been confirmed by immunofluorescence localization and have implications for intervention in the progression of AMD. Work is in progress to develop an assay to investigate drugs that could modulate this binding activity.