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; 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，途径和生物标记物 这可能使个人容易成为与年龄相关的黄斑变性（AMD），以便适当 可以开发预防和治疗靶标。通常，视网膜的退化已经 在诊所中被诊断为AMD时开始。大多数当前治疗都是针对的 新生血管AMD（一种疾病的高级和更严重的疾病），需要侵入性递送方法，是 限制其适用性，无法在长期内预防或逆转视力丧失。 AMD遗传学的重要工作已经建立了等位基因以及染色体1和10的单倍型， 特别是在CFH和LOC387715/ARMS2/HTRA1中，对人群中AMD风险的影响很大 各种种族。由于CFH的发现，对补体途径的进一步研究已有 揭示了C2/CFB，C3和CFH1-5中AMD风险与稀有等位基因之间的关联。虽然这些 研究说明了研究整个遗传途径的重要性，而不是孤立地研究一个基因 为常见疾病（例如AMD）开发有效的疗法，其中有许多无AMD的人 拥有这些疾病敏感性基因型/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有关AMD的见解 病因学，关于AMD风险和发病机理仍然有很多问题，无法解释 已知的AMD相关基因，因此重要的基因座仍有待鉴定和表征。在这个 竞争性更新提案，申请人，与来自不同学科的领先调查员合作 （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 使用表型良好的特征和文献记录的极端sibpairs的变体。方法 是多管齐下的，将采用艺术方法来指出与生物学相关的疾病靶标 他们的修饰符可能使人易于新生血管AMD。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 以及从链接，基因组宽之间基因组收敛的初步发现获得的基因 关于新生血管AMD风险的关联和基因表达分析。申请人预计 该项目将为对AMD发病机理的更好理解和 从而进一步发展治疗和预防这种疾病的策略。