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: 8556833
• 负责人: Chi-Chao Chan
• 金额: $ 100.08万
• 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/8556833
• 关键词: Age; Age related macular degeneration; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Archives; Ascaridil; Australia; Blindness; Candidate Disease Gene; Collaborations; DNA; Development; Disease; Elderly; Engineering; Enrollment; Extramural Activities; Eye; Gene Frequency; Genes; Genetic; Genetic Variation; Genets; Genotype; Goals; In Vitro; Individual; Inflammation; Lesion; Life; Manuscripts; MicroRNAs; Modeling; Molecular; Mus; Optical Coherence Tomography; Oxidative Stress; Paper; Paraffin; Pathogenesis; Patients; Pharmacogenomics; Population; Predisposition; Publishing; Recombinant Proteins; Recruitment Activity; Research Institute; Retina; Retinal; Role; Sampling; Single Nucleotide Polymorphism; Slide; TIMP3 gene; Therapeutic; Treatment Efficacy; Variant; Vision; aged; base; bevacizumab; gene environment interaction; gene interaction; genetic risk factor; in vivo; macrophage; material transfer agreement; neuroinflammation; pigment epithelium-derived factor; platelet-derived growth factor C; 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, 465 individuals have been enrolled and 107 histopathological cases with AMD have been collected. We continue to analyz 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from the AREDS project in USA. 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 (DKO rd8) mice) was generated to act as an AMD model in 2007. In FY2012, (1) we signed 2 additional material transfer agreements with 2 other extramural research institutes and transferred living DKO rd8 mice to them for collaborative studies of mechanisms and therapeutic options; (2) we continued characterizing DKO rd8 mice, a paper of 3D optical coherence tomography assessment (collaboration with Dr. Nicholas Bazan) was published (Zhou, et al. Exp Eye Res 2011;93:636-648); (3) we evaluated the anti-inflammatory and suppressive effect of TSG-6 recombinant protein (collaboration with Dr. Prockop) on the retinal lesions and published a paper (Tuo, et al. Neuroinflammation 2012;9:59). Currently, we are evaluating other compounds such as PDGF-CC (collaboration with Dr. Xuri Li), PEDF (collaboration with Dr. Becerra) and STC-1 (continue collaboration with Dr. Prockop) by using this animal model; (4) we provided DKO rd8 retina to collaborators for studies on microarray (collaboration with Dr. Mengqing Xiang and microRNA involvements in AMD (collaboration with Dr. Shusheng Wang); (5) using paraffin-embeded, archived slides, we studied the role of macrophage polarization in AMD and published our results (Cao, et al. Pathol Int 2011;61:528-535); (6) we conducted a pharmacogenomic study (collaboration with Drs. Catherine Meyerle, Richard Rosen and Shree Kurup) on the efficacy of anti-VEGF therapy on AMD and patients genotypes and currently have the manuscript under review in Molecular Vision; (7) we performed a large scale SNP association study on the role of TIMP3 in AMD and have the manuscript under review in Eur J Hum Genet; (8) we published a review paper on the genetics of inflammation in AMD (Tuo, et al. Ocul Immunol Inflamm 2012;20:27-36) and a chapter regarding the role of oxidative stress in DKO rd8 mice (Tuo. Chapt 17 in Studies on Retinal and Choroidal Disorders (Stratton, Hauswirth, Gardner, eds.) Humana Press, 2012, pp. 355-365).

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465名个体，并收集了107例AMD组织病理学病例。我们继续分析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（Ccl 2/Cx 3cr 1在rd 8背景上的双重缺陷（DKO rd 8）小鼠）以充当AMD模型。 在2012财政年度，（1）我们与另外两家校外研究机构签署了2份额外的材料转让协议，并将活体DKO rd 8小鼠转移给他们，以进行机制和治疗方案的合作研究;（2）我们继续表征DKO rd 8小鼠，3D光学相干断层扫描评估的论文（与Nicholas Bazan博士合作）（Zhou等人，Exp Eye Res 2011;93：636-648）;（3）评价TSG-6重组蛋白的抗炎和抑制作用Prockop博士合作），并发表了一篇论文（Tuo等人，Neuroinflammation 2012;9：59）。目前，我们正在评估其他化合物，如PDGF-CC（与李旭日博士合作），PEDF（与Becerra博士合作）和STC-1（继续与Prockop博士合作）;（4）我们向合作者提供DKO rd 8视网膜用于微阵列研究（与Mengqing Xiang博士合作，microRNA参与AMD研究（与Shusheng Wang博士合作）;（5）使用石蜡包埋的存档切片，我们研究了巨噬细胞极化在AMD中的作用，并发表了我们的结果。（Cao等人Pathol Int 2011;61：528-535）;（6）我们进行了药物基因组学研究（与Catherine Meyerle博士合作，Richard罗森和Shree Kurup）关于抗VEGF疗法对AMD的疗效和患者基因型的研究，目前该论文正在Molecular Vision上进行综述;（7）我们对TIMP 3在AMD中的作用进行了大规模SNP关联研究，并在Eur J Genet中对手稿进行了审查;（8）我们发表了关于AMD中炎症遗传学的综述论文（Tuo等人，Ocul Immunol Inflamm 2012;20：27-36）和关于氧化应激在DKO rd 8小鼠中的作用的章节（Tuo.第17章在视网膜和脉络膜疾病的研究（斯特拉顿，豪斯沃思，加德纳，编辑）Humana Press，2012，pp. 355-365）。