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).

与年龄相关的黄斑变性（AMD）导致全世界老年人口的不可逆转中心视觉丧失。各种研究表明AMD具有重要的遗传成分。当前的证据支持以下假设：基因变异会对该疾病产生倾向。 2003年，我们通过招募了患有正常视网膜的年龄匹配的对照组来启动该项目。最新的是，已经招募了482名个人，并收集了107例具有AMD的组织病理病例。我们继续分析澳大利亚蓝山眼研究的835个DNA样品的一部分，以及来自美国AREDS项目的534个DNA样品，因为某些DNA样品已经用完了。我们已经比较了AMD和对照受试者之间候选基因中单核苷酸多态性（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的遗传危险因素以及这些基因变异在疾病发病机理中的可能作用。基于从上述方法获得的信息，生成了基因工程动物（CCL2/CX3CR1双缺陷在RD8背景小鼠上，DKO RD8）在2007年起作用作为AMD模型。 在2013财年，（1）我们发布了使用DKO RD8鼠标模型作为AMD治疗筛选治疗化合物的平台的优点（Chu等，生物工程5：13-15，2013; Zhang等人Synapse 67：515-531，2013; Wang等人的Synapse 67：515-531; Wang等。 （2）我们通过评估PDGF-CC（与Xuri li博士的合作），PEDF（与S. Patricia Becerra博士的合作），与Darwin Prockop和Darwin Prockop合作（JEN NEURORED）：j NEUROINFLL：j NEUROINFLL：JE99599599999959.22 （Ramakumar等人Jutr 143：1129-1135，2013）。 AREDS II公式的作用已发表； （3）我们开始了一项抗体疗法的研究，以阻止DKO RD8小鼠视网膜组织中的Wnt途径（与Wen-Xin MA博士的合作）； （4）我们提供了DKO RD8视网膜来研究AMD中的MicroRNA角色（与Shusheng Wang博士的合作）； （5）我们报道了药物基因组学研究（与凯瑟琳·梅耶尔（Catherine Meyerle）博士，理查德·罗森（Richard Rosen）和什里·库鲁普（Shree Kurup）的合作）抗VEGF疗法对AMD和患者基因型的疗效（Wang等人，Mol Vis 18：2578-2585，2012）; （6）一项关于TIMP在AMD中作用的大规模SNP协会研究。关于DNA修复基因RAD51B在AMD中的作用的类似研究也已完成，并且该论文在Eur Hum Genet中（2013年2月20日。DOI：10.1038/ejhg.2013.14）; （7）。在此协议中招募的一些受试者进行了与AMD相关的基因型的筛选，并将与DRS合作在IPS项目中使用。 Sheldon Miller和Kapil Bharti； （8）我们根据基因表达使用了AMD的系统生物学亚型（Abu-Asab等人，Jophthalmology 2013，印刷中），并审查了如何区分AMD与衰老（Ardeljan，Prog Retin Eye。2013年8月9日。 （9）在此期间，我们总共发表了13篇相关或评论论文，包括AMD中IL17RC启动子低甲基化的新发现结果（与Lai Wei和Robert Nussenblatt博士合作：Cell Report 2：1151-1158，2012）和与AMD的合作：AMD Genee和Amd Anand Swarep博士和AMD ANAND SWAROP博士（AMD GeneT and Contibort） 45：433-439，2013）。