Age-Related Macular Degeneration: Genetic Variations and Animal Model

老年性黄斑变性（老年性黄斑变性，AMD）是世界上老年人群中导致不可逆中枢性视力丧失的主要原因。各种研究表明AMD有显著的遗传成分。目前的证据支持基因变异导致疾病易感性的假设。2003年，我们启动了这个项目，招募了晚期AMD患者和视网膜正常的年龄控制个体。迄今为止，已有373人被纳入研究，并收集了60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科研究的835份DNA样本和来自AREDS的534份DNA样本。我们比较了AMD和对照组之间候选基因内单核苷酸多态性（snp）的等位基因频率，并通过体外和/或体内实验对这些snp进行了功能研究。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2008财年，我们完成了以下工作：(1)建立了更高效的SNP分型新平台；(2)完成了HtrA1 SNP-环境相互作用的研究并在Ophthalmology上发表论文；(3)进一步表征了Ccl2/Cx3cr1双敲除（DKO）小鼠的视网膜病变- AMD小鼠模型；(4)完成了长链omega-3脂肪酸对DKO小鼠视网膜病变的影响测试，准备投稿。(5)开始通过体外和体内模型研究线粒体在AMD发病机制中的可能参与；(6)报道了ERp29在DKO和野生型小鼠视网膜色素上皮细胞中的差异表达，并在Current Eye Research上发表论文。

Age-related macular degeneration (AMD) is the leading cause of irreversible central visual loss in the aged population in the world. 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 age-control individuals with normal retinas. Up to date, 373 individuals have been enrolled and 60 histopathological cases with AMD have 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 FY2008, we have accomplished the following: (1) established an new platform for more efficient SNP typing, (2) completed the study on HtrA1 SNP-environmental interaction and published the paper in Ophthalmology, (3) further characterization of the retinal lesions in Ccl2/Cx3cr1 double knock-out (DKO) mice - a murine model of AMD, (4) completed to test the effect of long-chain omega-3 fatty acid on the retinal lesions of the DKO mice, a manuscript is prepared for submission, (5) started to investigate the the possible involvement of mitochondria in the AMD pathogenesis using in vitro and in vivo models, (6) reported differential expression of ERp29 in retinal pigment epithelial cells of DKO and wild type mice, and published a paper in Current Eye Research.