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

项目总结 老年性黄斑变性(AMD)是发达国家老年人致盲的主要原因 这是一个沉重的社会经济负担。尽管它的多面性很好 认识到，AMD的发病机制尚不完全清楚。这导致了目前缺乏治疗方法。 对于干性AMD，缺乏可靠的方法来确定进展的风险预测。因此，非常需要 更好地了解AMD的病理生物学和生物标志物的识别。 我们小组已经报告了(PMID 28542375、28916333和30672297)，并且有新的数据显示 代谢组学--代谢物(分子1 kDa)的定性和定量分析--是一种 采取适当的方法来满足这些需求。虽然代谢组在基因组的下游， 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，在复杂的条件下表现出来，例如 癌症和阿尔茨海默氏症。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，进行了眼科检查并收集了 禁食血样和尿样。对血液样本的分析确定了代谢组学特征的变化 AMD患者与对照组相比，不同AMD严重程度阶段的差异。这些差异 主要存在于脂质途径，特别是甘油磷脂和鞘磷脂，以及嘌呤。 在这项应用中，我们的目标是为AMD的发病机制提供新的见解，并确定 代谢信号可以导致这种疾病及其进展的未来生物标记物。要做到这一点，我们将 进一步鉴定AMD的代谢组。这将通过以下方式实现：1)执行组织代谢组学 AMD供眼和对照眼的质谱学检查(Aim 1A)，并评估相关性 AMD在组织和生物体液(即血浆和尿液)中的代谢谱之间的关系(目标1B)；2)Re- 评估我们的研究队列与早期和中期的AMD，在最初登记后五年，与 相同的方案，比较AMD进展者和非进展者的代谢组(目标2)； 研究与AMD风险相关的基因与代谢组学特征之间的关联(目标3A)，以及 确定新的代谢物-AMD相关性(目标3B)。 该项目将提供一种独特的策略，以增加目前对AMD发病机制的了解。 通过进行组织代谢组学和研究代谢组学-基因相互作用，这一建议将有助于 确定预防和早期干预的新目标，从而减轻AMD的负担。另外， 这项工作有可能确定AMD的生物标志物和疾病在五年内的进展 可获得的生物液，这可能有助于改善AMD的筛查和风险评估，并迎来 这种致盲疾病的精准医学时代。

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.