Biomarkers for Age-Related Macular Degeneration

老年性黄斑变性(AMD)是世界范围内导致失明的主要原因。在美国， 晚期AMD的患病率正在接近流行病的比例。建议的长期目标是 研究正在开发用于临床医学的预测技术，以评估AMD的风险 严重视力丧失，并监测AMD疗法的疗效。我们已经量化了血浆CEP 1400例AMD患者和对照组中4个AMD风险基因(羧乙基吡咯)生物标志物和基因分型 研究对象。那些CEP标志物和AMD风险基因升高的人患AMD的风险是2-3倍 比单纯基于基因的风险更大。一项相对较小的研究的初步发表结果 人群提示血浆蛋白羧甲基赖氨酸(CML)和戊糖苷显示AMD生物标志物 潜力。也就是说，CML和CEP加合物在AMD和对照受试者之间的区别大致相同 准确度(~78%)，戊糖苷(~88%)，CEP+戊糖苷(~92%)。 未发表的初步结果也表明CEP生物标记物在监测选择 AMD疗法和慢性粒细胞白血病和喷妥西丁在评估进展到 先进的干性AMD。我们假设血浆蛋白CEP、慢性粒细胞白血病和戊二醛与 基因组标志物将为评估严重视力丧失的风险提供临床上有用的预后测试 用于AMD和监测AMD的治疗。提出了两个具体的目标：(1)验证血浆蛋白 慢性粒细胞白血病和戊二胺作为AMD生物标记物在较大研究人群中的联合应用 AMD风险；以及(2)建立血浆蛋白CEP加合物的LC MS/MS分析，以提高准确性， 作为AMD风险预测因子的CEP测量的精确度和实用性。独特的资源，支持 建议的研究包括我们的大量临床记录的血浆库。 表征AMD和对照供体，我们最先进的蛋白质组、质谱学和基因组学 技术，在AMD生物学领域拥有十多年的经验和世界级的临床眼科和基础 视觉科学研究环境。 )

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. In the USA the prevalence of advanced AMD is approaching epidemic proportions. The long-term goal of the proposed research is the development of prognostic technology for use in clinical medicine to assess AMD risk for severe visual loss and to monitor the efficacy of AMD therapeutics. We have quantified plasma CEP (carboxyethylpyrrole) biomarkers and genotyped four AMD risk polymorphisms in over 1400 AMD and control subjects. The AMD risk for those exhibiting elevated CEP markers and AMD risk genotypes was 2-3 fold greater than the risk based on genotype alone. Preliminary published results from a relatively small study population suggest that plasma protein carboxymethyllysine (CML) and pentosidine exhibit AMD biomarker potential. Namely, CML and CEP adducts discriminate between AMD and control subjects with about equal accuracy (~78%), pentosidine with ~88% accuracy, and CEP plus pentosidine with ~92% accuracy. Unpublished preliminary results also indicate that CEP biomarkers have potential utility in monitoring select AMD therapeutics and that CML and pentosidine offer promise in assessing the risk of progression to advanced dry AMD. We hypothesize that plasma protein CEP, CML and pentosidine in combination with genomic markers will provide clinically useful prognostic tests for assessing the risk of severe visual loss due to AMD and for monitoring AMD therapeutics. Two specific aims are proposed: (1) Validate plasma protein CML and pentosidine as AMD biomarkers in a larger study population in combination with genomic markers of AMD risk; and (2) Develop a LC MS/MS assay for plasma protein CEP adducts to enhance the accuracy, precision and utility of CEP measurements as predictors of AMD risk. Unique resources supporting the proposed research include our large repository of plasma from clinically documented, extensively characterized AMD and control donors, our state-of-the-art proteomic, mass spectrometric and genomic technologies, over a decade of experience in AMD biology and a world-class clinical ophthalmology and basic vision science research environment. )