Sibling Study of Age-Related Macular Degeneration

年龄相关性黄斑变性的兄弟研究

• 批准号: 7655624
• 负责人: MARGARET M DEANGELIS
• 金额: $ 73.6万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655624
• 关键词: Age related macular degeneration; Alleles; Arts; Biological Assay; Biological Markers; Blindness; Candidate Disease Gene; Chromosomes, Human, Pair 1; Clinic; Collaborations; Coupled; Data; Development; Diagnosis; Discipline; Disease; Disease susceptibility; Elderly; Ethnic Origin; Etiology; Exudative age-related macular degeneration; Family; Foundations; Gene Expression; Genes; Genetic; Genome; Genomics; Genotype; Goals; Haplotypes; Individual; Investigation; Legal Blindness; Letters; Macular degeneration; Methodology; Methods; Molecular Genetics; Pathogenesis; Pathway interactions; Patients; Population; Prevention; Prevention therapy; Preventive; Proteomics; Research; Research Personnel; Retinal Degeneration; Risk; Role; Sampling; Siblings; Single Nucleotide Polymorphism; Solid; Susceptibility Gene; Therapeutic Intervention; Time; United States; Validation; Variant; Work; base; case control; cohort; complement pathway; cost; density; disorder prevention; effective therapy; genetic variant; genome wide association study; insight; meetings; prevent; therapeutic target

The overall goal of our research is to elucidate underlying mechanisms, pathways and biological markers which may predispose individuals to advanced age-related macular degeneration (AMD) so that appropriate preventive and therapeutic targets can be developed. Commonly, the degeneration of the retina has already begun by the time the patient is diagnosed with AMD in the clinic. Most current treatments are directed against neovascular AMD (an advanced and more severe form of the disease), require invasive delivery methods, are limited in their applicability, and not capable of preventing or reversing vision loss over the long term. Significant work in AMD genetics has established alleles as well as haplotypes on chromosomes 1 and 10, particularly in CFH and LOC387715/ARMS2/HTRA1, as having large influences on AMD risk in populations of various ethnicities. As a result of the CFH findings, further investigation of the complement pathway has revealed associations between AMD risk and rare alleles in the C2/CFB, C3 and CFH1-5. Although these studies illustrate the importance of studying entire genetic pathways rather than one gene in isolation to develop effective therapies for common diseases such as AMD, there are many AMD free individuals in the population that harbor these disease susceptibility genotypes/haplotypes and a substantial number of AMD patients who lack risk variants in these loci. While these findings have begun to provide insights into AMD etiology, there are still many questions about AMD risk and pathogenesis that cannot be explained by the known AMD-related genes and therefore important loci remain to be identified and characterized. In this competitive renewal proposal, the applicants, working with leading investigators from diverse disciplines (molecular genetics, statistical genetics and proteomics), aim to further identify and evaluate the role of genetic variants using a phenotypically well-characterized and documented cohort of extreme sibpairs. The approach is multi-pronged and will employ state of the art methodologies to pinpoint biologically relevant disease targets and their modifiers that may predispose an individual to neovascular AMD. To this end, the applicants will initially evaluate data from high density SNP/CNV arrays that are directly relevant to specific candidate regions and genes obtained from preliminary findings of genomic convergence between linkage, genome wide association and gene expression analysis on risk of neovascular AMD. The applicants anticipate that results of this project will provide a solid foundation on which to build a better understanding of AMD pathogenesis and thereby furthering the development of strategies for therapy and prevention of this disease.

我们研究的总体目标是阐明潜在的机制、途径和生物标记 这可能会使个体容易患上晚期年龄相关性黄斑变性（AMD），因此适当 可以制定预防和治疗目标。一般来说，视网膜已经退化 从患者在诊所被诊断患有 AMD 时开​​始。目前大多数治疗都是针对 新生血管性 AMD（该疾病的一种晚期且更严重的形式）需要侵入性输送方法， 它们的适用性有限，并且不能长期预防或逆转视力丧失。 AMD 遗传学领域的重大工作已经在 1 号和 10 号染色体上建立了等位基因和单倍型， 特别是在 CFH 和 LOC387715/ARMS2/HTRA1 中，因为对以下人群的 AMD 风险有很大影响 不同种族。根据 CFH 的研究结果，对补体途径的进一步研究已 揭示了 AMD 风险与 C2/CFB、C3 和 CFH1-5 中罕见等位基因之间的关联。虽然这些 研究表明研究整个遗传途径而不是孤立地研究一个基因的重要性 开发针对 AMD 等常见疾病的有效疗法，世界上有许多没有 AMD 的个体 携带这些疾病易感基因型/单倍型和大量 AMD 的人群 这些基因座缺乏风险变异的患者。虽然这些发现已开始为 AMD 提供深入见解 病因学方面，关于 AMD 的风险和发病机制仍然存在许多问题，无法用现有的方法来解释 已知的 AMD 相关基因以及重要的位点仍有待鉴定和表征。在这个 竞争性更新提案，申请人与来自不同学科的领先研究人员合作 （分子遗传学、统计遗传学和蛋白质组学），旨在进一步识别和评估遗传的作用 使用表型良好表征和记录的极端同胞对群体进行变体。方法 是多管齐下的，将采用最先进的方法来确定生物学相关的疾病目标 及其可能使个体易患新生血管性 AMD 的修饰因素。为此，申请人将 最初评估与特定候选区域直接相关的高密度 SNP/CNV 阵列的数据 以及从全基因组连锁之间基因组趋同的初步发现中获得的基因 新生血管性 AMD 风险的关联和基因表达分析。申请人预计结果 该项目将为更好地了解 AMD 发病机制和 从而进一步发展治疗和预防这种疾病的策略。