Metabolomic Signatures for Disease Sub-classification and Target Prioritization in AMP-AD

摘要： AMP-AD目标发现和临床前验证项目旨在缩短发现之间的时间 潜在的药物靶点和阿尔茨海默病(AD)治疗和治疗新药的开发 预防(RFA-AG-18-013)。AMP-AD下涉及的六个财团已经产生了大规模的分子 来自人脑样本的数据，采用网络建模方法和实验验证，定义 治疗AD的新的潜在药物靶点。下一阶段的主要挑战是提供更深层次的分子 了解与之相关的关键通路及其酶、转运体和信号分子 对药物发现工作负有责任。定义疾病内部异质性的分子基础对于 在精准医学背景下成功地进行药物开发。我们的AD代谢组学联盟(ADMC) 在第一阶段开始后一年成为AMP-AD的一部分，为这些努力增加了代谢组学的力量。 AD有发生在早期和症状前的基础代谢变化。大多数基因 与阿尔茨海默病有关提示在脂肪处理、免疫功能调节和吞噬功能中起作用，这些都是 与新陈代谢功能有关。详细的生物化学知识推动了医学领域的发展，为 监测疾病，如糖尿病和心血管疾病中的血糖和胆固醇的测量， 并导致药物的开发，如他汀类药物和抗抑郁药。在第一阶段，我们帮助定义 疾病的生化轨迹将外周和大脑的代谢变化连接到AMP-AD。我们建造了 AD早期变化的代谢网络与脑脊液和脑成像变化相关，定义性别 疾病的差异及其生化轨迹，确定肠道微生物群和肝脏在 认知功能减退、脑葡萄糖变化和萎缩，支持肠-肝-脑轴的重要性 在公元后。此外，我们还强调了两类可能的再利用药物(来自多发性硬化和脂肪肝 疾病)我们已经通知了AMP-AD内的其他三个财团关于他们的假定目标，支持他们 与生化途径的链接，并将看似不同的组学结果带到共同的生化 小路。在AMP-AD第二阶段，我们建议扩大代谢分析以加速AMP-AD 新药发现的进展。通过与AMP-AD合作伙伴合作，我们将系统地解决 外周代谢对大脑健康和疾病的贡献，并将提供生化读数作为 财团产生的丰富组学数据的中间表型。通过对样本进行分析和分析 来自症状前的大型社区研究，并建立了一个连接基因和 AD的代谢组学特征，我们希望提供关于AD的机制和亚类的生化见解 疾病。总而言之，ADMC将提供一个促进代谢互联的框架，以加速 AMP-AD的AD治疗进展。

ABSTRACT: The AMP-AD Target Discovery and Preclinical Validation Project aims to reduce the time between the discovery of potential drug targets and the development of new drugs for Alzheimer’s disease (AD) treatment and prevention (RFA-AG-18-013). The six involved consortia under AMP-AD have generated large-scale molecular data from human brain samples with network modeling approaches and experimental validation that defined novel potential drug targets for AD. A major challenge for the next phase is to provide a deeper molecular understanding of key implicated pathways and their enzymes, transporters and signaling molecules that are amenable for drug discovery efforts. Defining a molecular basis for heterogeneity within disease is critical for successful drug development within a precision medicine context. Our AD Metabolomics Consortium (ADMC) became part of AMP-AD one-year post inception of Phase I, adding the power of metabolomics to these efforts. AD has foundational metabolic changes that happen early and pre-symptomatically. Most of the genes implicated in AD suggest a role for lipid processing, immune function regulation, and phagocytosis that are all related to metabolic functions. Detailed biochemical knowledge advanced the medical field, providing tools for monitoring disease, such as measures of glucose and cholesterol in diabetes and cardiovascular diseases, and resulted in development of drugs, such as statins and antidepressants. In Phase I, we helped to define biochemical trajectories of disease bridging peripheral and brain metabolic changes to AMP-AD. We built metabolic networks for early changes in AD that correlate with CSF and brain imaging changes, defining sex differences and their biochemical trajectories of disease, identifying the role of the gut microbiome and liver in cognitive decline and brain glucose changes and atrophy, supporting the importance of the gut-liver-brain axis in AD. In addition, we have highlighted two classes of drugs for possible repurposing (from MS and fatty liver disease) We have informed three other consortia within AMP-AD about their putative targets, supporting them with links to biochemical pathways and bringing seemingly diverse omics findings to common biochemical pathways. During AMP-AD Phase II, we propose to expand metabolomic analyses to accelerate AMP-AD progress towards novel drug discovery. By working with AMP-AD partners, we will systematically address contributions of peripheral metabolism to brain health and disease and will provide biochemical readouts as an intermediate phenotype for rich omics data generated in the consortium. By profiling and analyzing samples from large community studies pre-symptomatically and by building an Atlas connecting genotypes and metabolomic signatures of AD we hope to provide biochemical insights about mechanisms and sub-classes of disease. In summary, the ADMC will provide an enabling metabolic interconnecting framework to accelerated AD therapeutic developing in AMP-AD.