Age-Related Macular Degeneration: Genetic Variations and Animal Model

老年性黄斑变性(AMD)是导致全球老年人群不可逆的中心性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，我们通过招募晚期AMD患者和视网膜正常的年龄控制者启动了这一项目。到目前为止，已经登记了419人，收集了60例AMD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AREDS历史上的NEI项目的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，我们已经确定了AMD的遗传危险因素，以及这些基因变异在疾病发病机制中的可能作用。根据上述方法获得的信息，已经产生了一种基因工程动物作为AMD模型。在2009财年，我们完成了以下工作：(1)建立了用于大规模数据分析的成熟的数据挖掘平台；(2)完成了HTRA1、TLR3和TLR4 SNP-AMD相关性的研究，并在眼科学和IOVS上发表了两篇论文；(3)完成了衣原体感染与AMD SNPs相互作用的研究，并在BJO上发表了结果；(4)进一步描述了CCL2/CX3CR1双基因敲除(DKO)小鼠-AMD小鼠模型的视网膜病变，并报道了Htra2/Omi参与了该模型的视网膜病变；(4)增加了长链omega-3脂肪酸对DKO小鼠视网膜损伤的检测实验，并在AJP上发表了这篇论文，(5)开始测试各种化合物和体内外(DKO)模型的基因治疗；(6)制定了7个物质转移协议(MTA)和1个合作研究与开发协议(CRADA)，供NIH和制药公司以外的研究人员将我们的DKO模型用于机械和治疗目的。

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, 419 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 a historical NEI project of 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 have identified genetic risk factors of AMD and the possible roles of these gene variations in the pathogenesis of the disease. Based on the information obtained from the above approches, a genetically engineered animal has been generated to act as the AMD model. In FY2009, we have accomplished the following: (1) established a sophisticated data mining platform for large scale data analysis; (2) completed the study on Htra1, TLR3 and TLR4 SNP-AMD association and published two papers in Ophthalmology and IOVS; (3) Completed the the study of the interation of Chlamydia infection and AMD SNPs and published the result in BJO; (4)further characterized the retinal lesions in Ccl2/Cx3cr1 double knock-out (DKO) mice - a murine model of AMD, and reported the involvement of Htra2/Omi in the retina lesion of the model; (4) Added the experiments on the test of long-chain omega-3 fatty acid on the retinal lesions of the DKO mice and published the paper in AJP, (5) started to test various compounds and gene therapy in vitro and in vivo (DKO) models; (6) creared 7 Material Transfer Agreetments (MTA), and 1 Collaborative Research and Development Agreement(CRADA) for researchers other than NIH and pharmaceutical company to use our DKO model for mechanistic and therapeutic purposes.