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: 10361569
• 负责人: Deeba Husain
• 金额: $ 40.76万
• 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/10361569
• 关键词: 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; 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; Lead; Life Style; Link; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Mediation; Methodology; Nature; Nonexudative age-related macular degeneration; Ophthalmology; 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; base; biomarker identification; cohort; 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 视网膜相关性黄斑变性（AMD）是发达国家老年人失明的主要原因。 这是一个巨大的社会经济负担。尽管它的多因素性质 虽然已经认识到，但AMD的发病机制尚未完全了解。这导致目前缺乏治疗方法 干性AMD和缺乏可靠的方法来确定进展的风险预测。因此，非常需要 更好地理解AMD病理生物学和鉴定生物标志物。 我们的小组已经报告（PMID 28542375、28916333和30672297），新数据显示 代谢组学-代谢物（分子<1 kDa）的定性和定量分析-是一种 采取适当的措施来满足这些需求。虽然代谢组位于基因组的下游， 转录组和蛋白质组，它同时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 癌症和老年痴呆症。为了评估代谢组学在AMD中的作用，我们启动了一项横断面研究， 在这项研究中，我们前瞻性地招募了491名患者，进行眼科检查，并收集 空腹血样和尿样血液样本的分析确定了代谢组学特征的变化 与对照组相比，AMD患者的AMD严重程度不同。这些差异 主要发现于脂质途径，特别是甘油磷脂和鞘脂以及嘌呤。 在这项申请中，我们的目标是提供新的见解AMD的发病机制，并确定 代谢组学信号可以导致这种疾病及其进展的未来生物标志物。为此，我们将 进一步表征AMD的代谢组。这将通过以下方式实现：1）在组织中进行组织代谢组学研究， 使用质谱法（Aim 1A）对患有AMD的供体眼和对照眼进行分析，并评估相关性 AMD在组织和生物流体（即血浆和尿液）中的代谢组学谱之间的关系（目的1B）; 2）重新- 评估我们的研究队列与早期和中期AMD，五年后，首次登记，与 相同的方案，以比较AMD进展者与非进展者的代谢组（目的2）;以及3） 研究与AMD风险相关的基因与代谢组学特征之间的关联（Aim 3A），以及 鉴定新的代谢物-AMD关联（目的3B）。 该项目将提供一个独特的策略，以增加目前的AMD发病机制的理解。 通过进行组织代谢组学和研究代谢组学-基因相互作用，这项建议将有助于 确定预防和早期干预的新目标，从而减轻AMD的负担。此外，本发明还 这项工作有可能在5年内确定AMD和疾病进展的生物标志物， 可获得的生物液体，这可能有助于改善AMD的筛查和风险评估，并迎来一个新的治疗方案。 精准医疗时代的到来