Carboxyethylpyrrole-Ethanolamine Phospholipids as AMD Biomarkers

羧乙基吡咯-乙醇胺磷脂作为 AMD 生物标志物

• 批准号: 9058079
• 负责人: JOHN W CRABB
• 金额: $ 19.81万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058079
• 关键词: Address; Affect; Age; Age related macular degeneration; Animals; Antioxidants; Binding; Biological Markers; Blindness; Blood; Bruch' s basal membrane structure; Choroid; Clinical assessments; Complement; Complement Factor H; Complex; Development; Diagnosis; Disease; Disease Progression; Docosahexaenoic Acids; Drusen; Elderly; Environment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Ethanolamines; Eye; Fluorometry; Future; Genetic; Genomics; Genotype; Goals; Health; Human; Image; Immune response; Individual; Inflammation; Inflammatory; Malondialdehyde; Mass Spectrum Analysis; Measures; Methodology; Methods; Modification; Monitor; N(6)-carboxymethyllysine; Ophthalmologist; Outcome; Oxidative Stress; Pathology; Patient Care; Patients; Pattern recognition receptor; Phosphatidylethanolamine; Phospholipids; Pilot Projects; Plasma; Plasma Proteins; Population; Post-Translational Protein Processing; Process; Proteins; Proteomics; Reactive Oxygen Species; Reporting; Research; Resources; Risk; Sampling; Smoking; Source; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Susceptibility Gene; TLR2 gene; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Treatment Efficacy; Vision research; Vitamins; advanced disease; amino group; angiogenesis; candidate marker; clinical care; experience; genomic biomarker; in vivo; macula; neovascularization; oxidation; pentosidine; potential biomarker; prevent; prognostic; protein biomarkers; protein crosslink; repository; risk variant; tool

 DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a complex disease and the leading cause of blindness in the elderly. Many individuals carrying AMD risk genotypes never develop the disease and only a fraction of those diagnosed with AMD progress to advanced disease with severe visual loss. Ophthalmologists cannot determine which patients will progress to advanced AMD. Our long-term goal is the development of prognostic technology for assessing advanced AMD risk and for monitoring AMD therapeutics. Our previous biomarker analyses have confirmed the AMD biomarker potential of plasma protein oxidative modifications such as carboxyethylpyrrole (CEP), carboxymethyllysine (CML) and pentosidine and that proteomic and genomic AMD biomarkers are more effective when used together than alone. We propose two exploratory aims that test the hypothesis that CEP-derivatives of ethanolamine phospholipids (CEP-EPs) are superior AMD biomarkers compared to CEP-protein modifications. Our preliminary studies suggest that like CEP-protein, CEP-EPs induce angiogenesis through toll-like receptor 2. Furthermore we have developed methodology for the efficient conversion of a multitude of CEP-EPs to a single derivative, namely CEP-ethanolamine (CEP-ETN) and have established a LC MS/MS method for quantifying CEP-ETN in plasma. Our pilot study measuring plasma CEP-ETN indicates CEP-EPs are much more elevated in AMD than normal plasma, more so than CEP-protein. In aim 1, we will validate by LC MS/MS elevated CEP-ETN in AMD plasma and demonstrate AMD biomarker utility both alone and in combination with genomic AMD markers and CEP-protein, CML and pentosidine. The results will enhance the discriminatory accuracy of AMD biomarkers. In aim 2, we will confirm that CEP-EP derivatives are elevated in AMD ocular tissues using MALDI imaging mass spectrometry, and establish quantifiable endpoints for future animal studies evaluating AMD therapeutics. Outstanding resources include a large, well-characterized plasma repository, the experience of the 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（由适用提供）：与年龄相关的黄斑变性（AMD）是一种复杂的疾病，并且是古老失明的主要原因。许多携带AMD风险基因型的人永远不会患上该疾病，只有被诊断为AMD进展为患有严重视觉损失的患有AMD的人的一小部分。眼科医生无法确定哪些患者将发展为晚期AMD。我们的长期目标是开发用于评估高级AMD风险和监测AMD治疗的预后技术。我们以前的生物标志物分析已经证实了血浆蛋白氧化修饰的AMD生物标志物潜在的潜力，例如羧甲基吡咯（CEP），羧甲基吡咯（CML）和戊烷以及蛋白质组学和基因组AMD生物标志物在使用时更有效时，在使用时更有效。我们提出了两个探索性目的，即检测乙醇胺磷脂（CEP-EPS）的CEP衍生物与CEP-蛋白质修饰相比是优质的AMD生物标志物。我们的初步研究表明，像CEP蛋白质，CEP-EPS一样，通过Toll样受体诱导血管生成2。此外，我们还开发了有效地转化多种CEP-EPS到单个衍生物，即CEP-ETN的方法，并建立了LC MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS/MS量化的方法。我们测量血浆CEP-ETN的试验研究表明，AMD中的CEP-EP比正常血浆升高得多，比CEP蛋白质更重要。在AIM 1中，我们将通过AMD等离子体中的LC MS/MS升高CEP-ETN验证，并与基因组AMD标记和CEP蛋白质，CML和五托氨酸一起证明AMD生物标志物实用程序。结果将提高AMD生物标志物的歧视精度。在AIM 2中，我们将确认使用MALDI成像质谱法在AMD眼组织中升高CEP-EP衍生物，并为评估AMD治疗的未来动物研究建立可量化的终点。杰出的资源包括一个大型，良好的等离子体存储库，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患者管理，因此总体影响将很高。