Sibling Study of Age-Related Macular Degeneration

我们研究的总体目标是阐明潜在的机制，途径和生物标志物 这可能使个体易患晚期年龄相关性黄斑变性（AMD）， 可以开发预防和治疗目标。一般来说，视网膜的退化已经 从患者在诊所被诊断为AMD时开始。目前大多数治疗方法都是针对 需要侵入性递送方法的新生血管性AMD（疾病的晚期和更严重的形式）， 它们的适用性有限，并且不能长期预防或逆转视力丧失。 AMD遗传学的重要工作已经在1号和10号染色体上建立了等位基因以及单倍型， 特别是在CFH和LOC 387715/ARMS 2/HTRA 1中，因为对以下人群中的AMD风险有很大影响： 不同的种族。作为CFH发现的结果，对补体途径的进一步研究 揭示了AMD风险与C2/CFB、C3和CFH 1 -5中罕见等位基因之间的关联。虽然这些 研究表明，研究整个遗传途径的重要性，而不是孤立地研究一个基因， 开发有效的治疗常见疾病，如AMD，有许多AMD免费的个人在 携带这些疾病易感性基因型/单倍型和大量AMD的人群 在这些基因座中缺乏风险变异的患者。虽然这些发现已经开始提供对AMD的见解 病因学方面，仍然有许多关于AMD风险和发病机制的问题无法通过 已知的AMD相关基因以及因此重要的基因座仍有待鉴定和表征。在这 有竞争力的续约提案，申请人，与来自不同学科的主要研究人员合作 （分子遗传学，统计遗传学和蛋白质组学），旨在进一步确定和评估遗传学的作用， 使用表型上充分表征和记录的极端同胞对的队列的变体。的方法 是多管齐下的，并将采用最先进的方法来确定生物相关的疾病目标 以及它们的修饰剂，其可使个体易患新生血管性AMD。为此，申请人将 最初评估来自与特定候选区域直接相关高密度SNP/CNV阵列的数据 以及从连锁、全基因组之间的基因组趋同的初步发现中获得的基因， 与新生血管性AMD风险的相关性和基因表达分析。申请人预计， 该项目将为更好地了解AMD发病机制提供坚实的基础， 从而进一步发展治疗和预防这种疾病的策略。

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.