Age-Related Macular Degeneration: Genetic Variations and Animal Model

年龄相关性黄斑变性：遗传变异和动物模型

• 批准号: 8737634
• 负责人: Chi-Chao Chan
• 金额: $ 79.19万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8737634
• 关键词: Age; Age related macular degeneration; Aging; Animal Model; Animals; Antibody Therapy; Apoptosis; Australia; Biomedical Engineering; Blindness; Candidate Disease Gene; Cells; Collaborations; DNA; DNA Repair Gene; Development; Disease; Elderly; Enrollment; Eye; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Engineering; Genetic Variation; Genets; Genotype; Goals; In Vitro; Individual; MicroRNAs; Modeling; Mus; Ophthalmology; Paper; Pathogenesis; Pathway interactions; Patients; Pharmacogenomics; Population; Predisposition; Printing; Protocols documentation; Publishing; Recruitment Activity; Reporting; Retina; Retinal; Role; Running; Sampling; Single Nucleotide Polymorphism; Synapses; Systems Biology; Therapeutic; Tissues; Treatment Efficacy; Variant; Work; aged; base; bevacizumab; gene environment interaction; gene interaction; genetic risk factor; in vivo; induced pluripotent stem cell; mouse model; novel; pigment epithelium-derived factor; platelet-derived growth factor C; promoter; research study; therapy development

Age-related macular degeneration (AMD) causes irreversible central visual loss in the aged population worldwide. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation creates a predisposition to the disease. In 2003, we initiated this project by recruiting advanced AMD patients and age-matched control individuals with normal retinas. Up to date, 482 individuals have been enrolled and 107 histopathological cases with AMD have been collected. We continue to analyze parts of 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from the AREDS project in USA because some DNA samples had been ran out. We have compared the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects, followed by 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 approaches, a genetically engineered animal (Ccl2/Cx3cr1 double deficiencies on rd8 background mice, DKO rd8) was generated to act as an AMD model in 2007. In FY2013, (1) we published the merits of using the DKO rd8 mouse model as a platform to screen therapeutic compounds for AMD treatment (Chu, et al. Bioengineered 5:13-15, 2013; Zhang, et al. Synapse 67:515-531, 2013; Wang, et al. Apoptosis 17:1144-1155, 2012); (2) we continue working with collaborators to use our DKO rd8 model to study disease pathogenesis and therapeutic options of AMD, by evaluating the roles of PDGF-CC (collaboration with Dr. Xuri Li), PEDF (collaboration with Dr. S. Patricia Becerra), TSG-6 (collaboration with Dr. Darwin Prockop: J Neuroinflamm e959, 2012) and AREDS II formula (Ramakumar, et al. J Nutr 143:1129-1135, 2013). The role of AREDS II formula has been published; (3) we initiated a study of antibody therapy to block WNT pathway in the retinal tissue of the DKO rd8 mice (collaboration with Dr. Wen-xin Ma); (4) we provided DKO rd8 retina for studying the microRNAs role in AMD (collaboration with Dr. Shusheng Wang); (5) we reported the pharmacogenomics study (collaboration with Drs. Catherine Meyerle, Richard Rosen and Shree Kurup) on the efficacy of anti-VEGF therapy on AMD and patients genotypes (Wang, et al. Mol Vis 18:2578-2585, 2012); (6) A large scale SNP association study on the role of TIMPs in AMD was published. A similar study on the role of DNA repair gene RAD51B in AMD is completed and the paper is in Eur Hum Genet (2013 Feb 20. doi: 10.1038/ejhg.2013.14); (7). some subjects recruited in this protocol were screened for their AMD related genotypes and will be used in the iPS project in collaboration with Drs. Sheldon Miller and Kapil Bharti; (8) we used a systems biology subtyping of AMD on the basis of gene expression (Abu-Asab, et al. J Ophthalmology 2013, in press) and reviewed how to distinguish AMD from aging (Ardeljan, Prog Retin Eye Res. 2013 Aug 9. doi:pii: S1350-9462(13)00045-1 Epub ahead of print); (9) in this period, we published a total of 13 relevant original or review papers including the novel findings of hypomethylation of the IL17RC promoter in AMD (collaboration with Dr. Lai Wei & Robert Nussenblatt: Cell Report 2:1151-1158, 2012) and the 7 new loci associated with AMD (collaboration with Dr. Anand Swaroop and the AMD Gene Consortium: Nat Genet 45:433-439, 2013).

视网膜相关性黄斑变性（AMD）在世界范围内的老年人群中引起不可逆的中心视力丧失。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，即基因变异导致了这种疾病的易感性。在2003年，我们通过招募晚期AMD患者和年龄匹配的正常视网膜对照个体启动了该项目。到目前为止，已招募了482名个体，并收集了107例AMD组织病理学病例。由于部分DNA样本已经用完，我们继续分析了来自澳大利亚蓝山眼科研究的835份DNA样本和来自美国AREDS项目的534份DNA样本。我们比较了AMD和对照受试者之间候选基因内单核苷酸多态性（SNP）的等位基因频率，然后通过体外和/或体内实验对这些SNP进行功能研究。通过这种方法，我们已经确定了AMD的遗传风险因素和这些基因变异在疾病发病机制中的可能作用。基于从上述方法获得的信息，在2007年产生了基因工程动物（在rd 8背景小鼠上的Ccl 2/Cx 3cr 1双缺陷，DKO rd 8）以充当AMD模型。 在2013财年，（1）我们发表了使用DKO rd 8小鼠模型作为平台筛选治疗AMD的治疗化合物的优点（Chu等Bioengineered 5：13-15，2013; Zhang等Synapse 67：515-531，2013; Wang等Apoptosis 17：1144-1155，2012）;（2）我们继续与合作者合作，使用我们的DKO rd 8模型来研究AMD的疾病发病机制和治疗选择，通过评估PDGF-CC（与李旭日博士合作）、PEDF（与S. Patricia Becerra）、TSG-6（与Dr.达尔文Prockop合作：J Neuroinflamm e959，2012）和AREDS II配方（Ramakumar等人，J Nutr 143：1129-1135，2013）。AREDS II配方的作用已发表;（3）我们开始了抗体治疗的研究，以阻断DKO rd 8小鼠视网膜组织中的WNT通路（与马文新博士合作）;（4）我们提供DKO rd 8视网膜用于研究microRNA在AMD中的作用（与王树生博士合作）;（5）药物基因组学研究（与Catherine Meyerle、Richard罗森和Shree Kurup博士合作）关于抗VEGF治疗对AMD和患者基因型的疗效（Wang等，Mol维斯18：2578-2585，2012）;（6）发表了关于TIMP在AMD中的作用的大规模SNP关联研究。关于DNA修复基因RAD 51 B在AMD中的作用的类似研究已经完成，该论文发表在Eur Genet（2013年2月20日）上。doi：10.1038/ejhg.2013.14）;（7）.对本方案中招募的一些受试者进行了AMD相关基因型筛选，并将与谢尔顿米勒和Kapil Bharti博士合作用于iPS项目;（8）采用基于基因表达的AMD系统生物学亚型（Abu-Asab等人，J Ophthalmology 2013，出版中），并综述了如何区分AMD与衰老（Ardeljan，Prog Retin Eye Res.2013 Aug 9. doi：pii：S1350-9462（13）00045-1 Epub ahead of print）;（9）在这一时期，我们共发表了13篇相关的原创或综述论文，包括AMD中IL 17 RC启动子低甲基化的新发现（与Lai Wei博士和Robert Nussenblatt合作：Cell Report 2：1151-1158，2012）和与AMD相关的7个新基因座（与Anand Swaroop博士和AMD基因联盟合作：Nat Genet 45：433-439，2013）。