Metabolomics a Novel Tool for Investigating the Pathogenesis of Age-related Macular Degeneration

代谢组学是研究年龄相关性黄斑变性发病机制的新工具

• 批准号: 10579904
• 负责人: Deeba Husain
• 金额: $ 42万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579904
• 关键词: Acceleration; Address; Affect; Age; Age related macular degeneration; Alzheimer' s Disease; Biological; Biological Markers; Biometry; Blindness; Blood; Blood specimen; Characteristics; Clinical; Cohort Studies; Complex; Cross-Sectional Studies; Data; Databases; Developed Countries; Development; Diagnosis; Disease; Disease Progression; Early Intervention; Early treatment; Economic Burden; Elderly; Environmental Exposure; Environmental Risk Factor; Exhibits; Eye; Fasting; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Genome; Genomics; Glycerophospholipids; Goals; Heritability; In Situ; Individual; Knowledge; Life Style; Link; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Mediation; Methodology; Nature; Nonexudative age-related macular degeneration; Pathogenesis; Pathway interactions; Patients; Performance; Phenotype; Plasma; Prevention; Proteome; Protocols documentation; Purines; Quantitative Trait Loci; Reporting; Risk; Risk Assessment; Role; Sampling; Severities; Signal Transduction; Single Nucleotide Polymorphism; Sphingolipids; Statistical Methods; Tissues; Transcription Process; Urine; Work; biomarker identification; cohort; comparison control; design; disorder of macula of retina; gene interaction; genetic epidemiology; genetic profiling; genome wide association study; genome-wide; genomic locus; human tissue; improved; insight; metabolic profile; metabolome; metabolomics; multidisciplinary; novel; novel strategies; potential biomarker; precision medicine; preventive intervention; profiles in patients; progression marker; prospective; recruit; risk prediction; screening; small molecule; socioeconomics; statistics; study population; tool; transcriptome; urinary

PROJECT SUMMARY Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in developed nations, representing a significant socioeconomic burden. Even though its multifactorial nature is well recognized, the pathogenesis of AMD is not fully understood. This has led to the current absence of treatments for dry AMD and lack of reliable ways to determine risk prediction for progression. Thus, there is great need for better understanding of AMD pathobiology and identification of biomarkers. Our group has reported (PMID 28542375, 28916333 and 30672297) and there is new data showing that metabolomics—the qualitative and quantitative analysis of metabolites (molecules <1 kDa)—is an appropriate approach to address these needs. While the metabolome is downstream of the genome, transcriptome, and proteome, it is simultaneously impacted by a wide range of environmental exposures. Therefore, the metabolome closely represents phenotype, as demonstrated in complex conditions, such as cancer and Alzheimer’s disease. To evaluate the role of metabolomics in AMD, we initiated a cross sectional study in which we prospectively recruited 491 patients, obtained an ophthalmological exam and collected fasting blood and urine samples. Analysis of the blood samples identified changes in the metabolomics profile of patients with AMD compared to controls, with differences across AMD severity stages. These differences were mostly found in the lipid pathways, in particular glycerophospholipids and sphingolipids, and purines. In this application, our goal is to provide novel insights into the pathogenesis of AMD, and to identify metabolomic signals that can lead to future biomarkers of this disease and its progression. To do so, we will further characterize the metabolome of AMD. This will be achieved by: 1) performing tissue metabolomics in donor eyes with AMD and control eyes using mass spectrometry (Aim 1A), and assessing correlations between the metabolomic profiles of AMD in tissue and biofluids (i.e. plasma and urine) (Aim 1B); 2) re- assessing our study cohort with early and intermediate AMD, five years after the initial enrolment, with the same protocols, to compare the metabolome of AMD-progressors versus non progressors (Aim 2); and 3) studying the associations between genes linked with AMD risk and metabolomics profiles (Aim 3A), and identifying new metabolite-AMD associations (Aim 3B). This project will provide a unique strategy to increase the current understanding of AMD pathogenesis. By performing tissue metabolomics and studying metabolomics-gene interactions, this proposal will help in identifying new targets for prevention and earlier intervention, thus reducing the burden of AMD. Additionally, this work has the potential to identify biological biomarkers of AMD and disease progression at five years in accessible biofluids, which may contribute to improved screening and risk assessment of AMD and usher in an era of precision medicine for this blinding condition.

项目摘要 与年龄相关的黄斑变性（AMD）是发育中的盲目性的主要原因 国家，代表着重大的社会经济负担。即使其多因素性质很好 认识到，AMD的发病机理尚未完全理解。这导致当前没有治疗 对于干燥的AMD和缺乏确定进展风险预测的可靠方法。那非常需要 更好地了解AMD病理生物学和生物标志物的识别。 我们的小组报告了（PMID 28542375、28916333和30672297），还有新的数据显示 该代谢组学 - 代谢物的定性和定量分析（分子<1 kDa） - 是一个 适当的方法来满足这些需求。虽然代谢组是基因组的下游，但 转录组和蛋白质组，它只是受到广泛的环境暴露的影响。 因此，代谢组密切代表表型，如在复杂条件下所证明的，例如 癌症和阿尔茨海默氏病。为了评估代谢组学在AMD中的作用，我们启动了一个横截面 我们前瞻性招募了491名患者，获得了眼科检查并收集的研究 禁食的血液和尿液样本。对血液样本的分析确定了代谢组学的变化 与对照组相比，AMD患者的患者在AMD严重程度阶段的差异。这些差异 它们主要是在脂质途径中发现的，尤其是甘油磷脂和鞘脂的途径以及王子。 在此应用中，我们的目标是提供有关AMD发病机理的新见解，并确定 代谢组信号可能导致这种疾病的未来生物标志物及其进展。为此，我们会 进一步描述了AMD的代谢组。这将通过以下方式实现：1）在 使用质谱法（AIM 1A）和评估相关性的供体眼睛和对照眼对照眼睛 在组织和生物流体（即血浆和尿液）中AMD的代谢组谱之间（AIM 1B）； 2）重新 在初始信封五年后，与早期和中级AMD评估我们的研究队列 相同的协议，以比较AMD-rogressor的代谢组与非进步者的代谢组（AIM 2）； 3） 研究与AMD风险和代谢组学概况相关的基因之间的关联（AIM 3A）和 识别新的代谢物-AMD关联（AIM 3B）。 该项目将提供一种独特的策略，以增加对AMD发病机理的当前理解。 通过进行组织代谢组学和研究代谢组学 - 基因相互作用，该建议将有助于 确定预防和较早干预的新目标，从而减少了AMD的燃烧。此外， 这项工作有可能在五年内识别AMD和疾病进展的生物学生物标志物 可访问的生物流体，这可能有助于改善对AMD和USHER的筛查和风险评估 这种盲人的精确医学时代。