Proteomic Biomarkers for AMD

AMD 的蛋白质组生物标志物

• 批准号: 8586525
• 负责人: JOHN W CRABB
• 金额: $ 19.23万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586525
• 关键词: Age related macular degeneration; Aqueous Humor; Biological Markers; Biology; Blindness; Blood; Blood Circulation; Blood specimen; Bruch' s basal membrane structure; Cardiovascular system; Cataract Extraction; Choroid; Clinical; Collection; Complex; Data; Development; Disease; Elderly; Environment; Evaluation; Eye; Genomics; Genotype; Glaucoma; Goals; Health; Immune response; Individual; Inflammatory; Inflammatory Response; Lead; Medicine; Methods; Molecular; Monitor; Ophthalmologist; Ophthalmology; Pathology; Patient Care; Patients; Plasma; Plasma Proteins; Process; Progressive Disease; Proteins; Proteome; Proteomics; Relative (related person); Research; Resources; Risk; Specimen; Structure of sinus venosus of sclera; Technology; Testing; Therapeutic; Tissues; Trabecular meshwork structure; Vascular Endothelial Growth Factors; Veins; Vision; Vision research; advanced disease; anterior chamber; base; complement system; experience; improved; insight; macula; molecular marker; outcome forecast; prevent; prognostic; public health relevance; ranibizumab; repository; risk variant; vision science

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.

描述（由申请人提供）：与年龄相关的黄斑变性（AMD）是全球失明的主要原因。只有一小部分AMD患者发展为晚期疾病，眼科医生无法预测哪些患者将进步。临床预后需要客观的分子标记来预防或缓慢视力丧失。仅基因组标记不足，因为许多携带AMD风险基因型的个体永远不会产生视力受损。各种机制驱动AMD进展，并且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治疗剂的分子技术。我们提出了两个探索性蛋白质组学目标，这些蛋白质组学目标将导致一组AMD蛋白生物标志物的发展。在AIM 1中，我们将测试以下假设：黄斑AMD BRUCH的膜脉络膜复合物中改变的蛋白质提供了AMD风险的血浆生物标志物。我们已经确定了AMD黄斑组织中的99个蛋白质生物标志物候选物，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物。在AIM 2中，我们将检验以下假设：幽默（AH）蛋白质组为AMD机制和生物标志物提供了新的见解。 AMD改变的蛋白在AH中的浓度比血浆中的浓度更高，并且更容易检测到。 AH和血液标本将从白内障手术中获得。 LC MS/MS ITRAQ技术将对AH进行全球定量蛋白质组学分析。结果将促进血浆中的靶向定量蛋白质组学分析，因为BRUCH脉络膜和AH中AMD的蛋白质改变了蛋白质，可能会在血浆中提供高AMD歧视潜力。我们拥有大型基因分型标本的AMD血浆存储库，蛋白质组学结果将与AMD风险基因型相关。其他杰出的资源包括转化调查团队的经验以及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患者管理，因此总体影响将很高。