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: 8339775
• 负责人: Chi-Chao Chan
• 金额: $ 104.89万
• 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/8339775
• 关键词: Age; Age related macular degeneration; Aging; Animal Model; Animals; Australia; Blindness; Book Chapters; Candidate Disease Gene; Collaborations; Copy Number Polymorphism; DNA; Data; Development; Disease; Elderly; Engineering; Enrollment; Epigenetic Process; Extramural Activities; Eye; Gene Frequency; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; In Vitro; Individual; Lesion; Life; Mesenchymal Stem Cells; Microglia; Modeling; Mus; Naloxone; Paper; Pathogenesis; Patients; Pharmacogenomics; Population; Predisposition; Proteins; Publishing; Recruitment Activity; Reporting; Research Institute; Retina; Retinal; Role; Sampling; Single Nucleotide Polymorphism; Synapses; Testing; Therapeutic; Thromboplastin; Treatment Efficacy; Variant; aged; base; bevacizumab; gene environment interaction; gene interaction; gene therapy; genetic risk factor; genome wide association study; in vivo; material transfer agreement; pigment epithelium-derived factor; platelet-derived growth factor C; research study

Age-related macular degeneration (AMD) causes irreversible central visual loss in the aged population. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation places 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, 449 individuals have been enrolled and 107 histopathological cases with AMD have been collected. We continue analyzing 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from a historical AREDS in USA. 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 approaches, a genetically engineered animal has been generated to act as the AMD model. In FY2011, (1) We created material transfer agreements with 3 additional extramural research institutes and sent them living mice (ccl2/cx3cr1 deficiency) to study mechanism and therapeutic options for AMD; (2) Using previous established platforms, we completed the study on copy number variation of 8 genes and AMD association. The result has been published in IOVS; (3) We continued characterizing ccl2/cx3cr1 deficient mice, a murine model of AMD, in ultrastructure. We found pathological changes in synapse and tissue factor expression on the retinal lesions of these mice. We reported the synapse data in ARVO 2011 and published the result of tissue factor in full article; (4) We evaluated the suppressive effect of naloxone on the lesions by targeting microglia and evaluated AAV-sFLT01 gene therapy in the ccl2/cx3cr1 deficient mice and published the results in two articles (Shen, IOVS and Tuo, Neurobiol Aging). Currently, we are testing the effects of other compounds such as PDGF-CC and PEDF by using this animal model. In a collaboration with Dr. Prockop, we tested the effect of TSG-6, a secreted protein from the mesenchymal stem cells on the retinal lesion of ccl2/cx3cr1 deficient mice and reported in ARVO 2011; (5) We conducted a pharmacogenomic study on the relationship between the efficacy of anti-VEGF therapy on AMD and patients genotypes and results were presented in ARVO 2011; (6) We provided the genomic material to collaborators for studies on epigenetic and immunological involvements in AMD, and verification of Genome-Wide Association Study; (7) Three invited review papers were published and two book chapters were prepared.

年龄相关性黄斑变性（AMD）会导致老年人不可逆的中央视力丧失。各种研究表明，AMD 具有重要的遗传因素。目前的证据支持基因变异导致该疾病易感性的假设。 2003 年，我们启动了这个项目，招募了晚期 AMD 患者和年龄匹配、视网膜正常的对照个体。截至目前，已入组449人，收集AMD组织病理学病例107例。我们继续分析来自澳大利亚蓝山眼科研究的 835 个 DNA 样本和来自美国历史 AREDS 的 534 个 DNA 样本。我们正在比较 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，我们确定了 AMD 的遗传风险因素以及这些基因变异在该疾病发病机制中的可能作用。基于从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。 2011财年，（1）我们与另外3个校外研究机构签订了材料转让协议，并向其送去活体小鼠（ccl2/cx3cr1缺陷）来研究AMD的机制和治疗方案； (2)利用已有平台，完成了8个基因拷贝数变异与AMD关联的研究。结果已发表在IOVS上； (3) 我们继续表征 ccl2/cx3cr1 缺陷小鼠（AMD 的小鼠模型）的超微结构。我们发现这些小鼠视网膜病变上突触和组织因子表达的病理变化。我们在ARVO 2011报道了突触数据，并全文发表了组织因子的结果； (4) 我们评估了纳洛酮通过靶向小胶质细胞对病变的抑制作用，并在 ccl2/cx3cr1 缺陷小鼠中评估了 AAV-sFLT01 基因治疗，并将结果发表在两篇文章中（Shen, IOVS 和 Tuo, Neurobiol Aging）。目前，我们正在利用该动物模型测试PDGF-CC和PEDF等其他化合物的效果。在与 Prockop 博士的合作中，我们测试了 TSG-6（一种间充质干细胞分泌的蛋白质）对 ccl2/cx3cr1 缺陷小鼠视网膜病变的影响，并在 ARVO 2011 中进行了报道； (5) 我们对抗VEGF治疗AMD的疗效与患者基因型之间的关系进行了药物基因组学研究，结果发表在ARVO 2011上； （6）我们向合作者提供基因组材料，用于AMD的表观遗传和免疫学参与研究，以及全基因组关联研究的验证； （7）发表特邀评论论文三篇，编写书籍章节两篇。