Proteomic Biomarkers for AMD

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是全球失明的主要原因。只有一小部分AMD患者进展为晚期疾病，眼科医生无法预测哪些患者会进展。临床预后需要客观的分子标记物来预防或减缓视力丧失。基因组标记本身是不够的，因为许多携带AMD风险基因型的个体从未出现视力受损。不同的机制驱动AMD的进展，需要多种生物标志物来优化患者护理。我们的长期目标是开发用于评估AMD风险和监测AMD治疗的分子技术。我们提出了两个探索性的蛋白质组学目标，这将导致一组AMD蛋白质生物标志物的发展。在目的1中，我们将验证黄斑AMD Bruch膜脉络膜复合体中改变的蛋白质提供AMD风险的血浆生物标志物的假设。我们已经在AMD黄斑组织中确定了99个候选蛋白生物标志物，并将通过靶向LC MS/MS定量蛋白质组学在血浆中验证这些候选蛋白。在目标2中，我们将验证房水蛋白组为AMD机制和生物标志物提供新见解的假设。AMD改变的蛋白在AH中的浓度比在血浆中的浓度更高，也更容易检测到。白内障手术将获得AH和血液标本。采用LC MS/MS iTRAQ技术对AH进行全局定量蛋白质组学分析。结果将有助于对血浆中AMD的定量蛋白质组学分析，因为AMD改变了Bruch脉络膜和AH中的蛋白质，可能会在血浆中提供高的AMD区分电位。我们有一个大型的AMD血浆基因型样本库，蛋白质组学结果将与AMD风险基因型相关。其他优秀的资源包括翻译调查团队的经验和世界一流的视觉研究环境。由于有效的生物标志物将改变AMD患者的管理，因此整体影响将很高。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Only a fraction of AMD patients progress to advanced disease and ophthalmologists cannot predict which patients will advance. Objective molecular markers are needed for clinical prognostics to prevent or slow vision loss. Genomic markers alone are insufficient as many individuals carrying AMD risk genotypes never develop impaired vision. Diverse mechanisms drive AMD progression and multiple biomarkers are needed for optimized patient care. Our long-term goal is the development of molecular technology for assessing AMD risk and monitoring AMD therapeutics. We propose two exploratory proteomic aims that will lead to the development of a panel of AMD protein biomarkers. In aim 1, we will test the hypothesis that proteins altered in macular AMD Bruch's membrane choroid complex provide plasma biomarkers of AMD risk. We have already identified 99 protein biomarker candidates in AMD macular tissues, and will validate these candidates in plasma by targeted LC MS/MS quantitative proteomics. In aim 2, we will test the hypothesis that the aqueous humor (AH) proteome offers new insights to AMD mechanisms and biomarkers. AMD altered proteins will be at higher concentrations in AH than in plasma and more readily detectable. AH and blood specimens will be obtained from cataract surgeries. Global quantitative proteomic analysis of AH will be pursued by LC MS/MS iTRAQ technology. Results will facilitate targeted quantitative proteomic analyses in plasma as AMD altered proteins in both Bruch's choroid and AH likely will provide high AMD discriminatory potential in plasma. We have a large AMD plasma repository of genotyped specimens and proteomic results will be correlated with AMD risk genotypes. Other outstanding resources include the experience of the translational investigative team, and a world-class vision research environment. The overall impact will be high as effective biomarkers will transform AMD patient management.