Age-Related Macular Degeneration: Genetic Variations and Animal Model

老年性黄斑变性(AMD)是导致老年人严重中心视力丧失的主要原因。各种研究表明，AMD具有重要的遗传成分。目前的证据支持这样一种假设，即基因变异导致疾病的易感性。2003年，我们招募了晚期AMD患者和视网膜正常的对照组，启动了这一项目。到目前为止，已有400多名受试者入选，并收集了80例AMD的组织病理学病例。我们还收到并分析了来自澳大利亚蓝山眼研究的835个DNA样本和来自AREDS的534个DNA样本。我们正在比较AMD和对照组候选基因中单核苷酸多态(SNPs)的等位基因频率，然后通过体外和/或体内实验对这些SNPs的功能进行研究。通过这种方法，我们可以识别AMD的遗传危险因素，并了解这些基因变异在疾病发病机制中的作用。根据从上述实验和最近的文献中获得的信息，已经产生了一种基因工程动物作为疾病模型。在2007财年，我们完成了以下工作：(1)完成了6,000个SNPs基因分型；(2)在4个队列中确认和完善了HtrA1与AMD的关联；(3)发表了CCL2/CX3CR1双基因敲除(DKO)小鼠的视网膜病变特征-AMD的小鼠模型；(4)证实并发表了ARMS2(LOC387715)与AMD的关联；(5)证实了ER蛋白参与了AMD的发病机制，(6)开始将DKO动物模型应用于长链omega-3脂肪酸喂养和药物伴侣分子Gavarge的干预研究；(7)建立了永生化视网膜色素上皮细胞系，为以后的实验做准备。

Age-related macular degeneration (AMD) is the leading cause of irreversible severe central visual loss in the aged population. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation causes a predisposition to the disease. In 2003, we initiated this project by recruiting advanced AMD patients and controls with normal retinas. Up to date, over 400 subjects have been enrolled and 80 histopathological cases with AMD hae been collected. We also received and analyzed 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from AREDS. We are comparing the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects followed by the functional studies of these SNPs by in vitro and/or in vivo experiments. Through this approach, we can identify genetic risk factors of AMD and understand the role of these gene variations in the pathogenesis of the disease. Based on the information obtained from the above experiments and recent literature, a genetically engineered animal has been generated to act as the disease model. In FY2007, we have accomplished the following: (1) completed 6,000 SNPs genotypes, (2) confirmed and refined the HtrA1 AMD association in 4 cohorts and reported at international and national scientific meetings, (3) published the characterization of the retinal lesions in Ccl2/Cx3cr1 double knock-out (DKO) mice - a murine model of AMD, (4) confirmed and published ARMS2 (LOC387715) association with AMD, (5) confirmed the involvement of ER protein in the pathogenesis of AMD, (6) started to apply the DKO animal model in intervention studies of the long-chain omega-3 fatty acid feeding and pharma-chaperone molecule gavarge, (7) established an immortalized retinal pigmented epithelium cell lines for future experiments.