Metabolomic Signatures for Disease Sub-classification and Target Prioritization in AMP-AD
AMP-AD 中疾病亚分类和目标优先级的代谢组学特征
基本信息
- 批准号:9789158
- 负责人:
- 金额:$ 150.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAminesAnimalsAntidepressive AgentsAtlasesAtrophicBile AcidsBindingBiochemicalBiochemical PathwayBiological MarkersBiological ModelsBlood specimenBrainBrain DiseasesBrain imagingBranched-Chain Amino AcidsCardiovascular DiseasesChemicalsCholesterolClassificationClinicalClinical TrialsCognitionCognitiveCommunitiesDataDatabasesDevelopmentDiabetes MellitusDiseaseDrug TargetingDrug usageEarly InterventionEnzymesFailureFatty LiverFluorouracilFoundationsFramingham Heart StudyFunctional disorderGene ExpressionGenesGeneticGenetic VariationGenomeGenotypeGlucoseGlutamatesGoalsHeterogeneityHumanImpaired cognitionKnowledgeLeadLecithinLife StyleLinkLipidsLiverLiver diseasesMalignant NeoplasmsMeasuresMedicalMetabolicMetabolic PathwayMetabolismMolecularMonitorNetwork-basedNeurotransmittersPathogenesisPathway interactionsPatientsPeripheralPhagocytosisPharmaceutical PreparationsPhasePhenotypePreventionProxyRegulationResearchRiskRisk FactorsRoleSamplingSex DifferencesSignal TransductionSignaling MoleculeSphingomyelinsStratificationStructureSymptomsTherapeuticTimeTranslationsTryptophanTyrosineValidationVertebral columnbiomarker developmentbrain healthclinical phenotypeclinical subtypescohortcytotoxicdisease phenotypedisorder subtypedrug developmentdrug discoverygut microbiomehuman dataimmune functioninsightmetabolic phenotypemetabolomicsmolecular scalenetwork modelsneuroimagingnew therapeutic targetnovelnovel therapeuticspre-clinicalprecision medicineprotein expressionresearch clinical testingsextooltreatment response
项目摘要
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.
摘要:
AMP-AD靶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)治疗新药的开发,
预防(RFA-AG-18-013)。AMP-AD下的六个相关财团已经产生了大规模的分子生物学。
数据从人脑样本与网络建模方法和实验验证,定义
AD的新的潜在药物靶点。下一阶段的一个主要挑战是提供一个更深入的分子
了解关键的相关途径及其酶,转运蛋白和信号分子,
适合药物发现工作。确定疾病内异质性的分子基础对于
在精准医疗背景下成功开发药物。我们的AD代谢组学联盟(ADMC)
在第一阶段开始一年后成为AMP-AD的一部分,为这些努力增加了代谢组学的力量。
AD具有早期和发病前发生的基础代谢变化。大多数基因
提示与AD有关脂质加工、免疫功能调节和吞噬作用,
与代谢功能有关。详细的生物化学知识推动了医学领域的发展,
监测疾病,例如糖尿病和心血管疾病中的葡萄糖和胆固醇的测量,
并导致药物的开发,如他汀类药物和抗抑郁药。在第一阶段,我们帮助定义了
疾病的生化轨迹将外周和脑代谢变化与AMP-AD联系起来。我们建立
与CSF和脑成像变化相关的AD早期变化的代谢网络,定义性别
差异及其疾病的生化轨迹,确定肠道微生物组和肝脏在
认知能力下降和脑葡萄糖变化和萎缩,支持肠-肝-脑轴的重要性
在AD中。此外,我们强调了两类可能重新利用的药物(来自MS和脂肪肝
疾病)我们已经通知了AMP-AD中的其他三个财团关于他们的假定目标,支持他们
与生物化学途径的联系,并将看似多样化的组学发现带到常见的生物化学途径中,
途径。在AMP-AD II期,我们建议扩大代谢组学分析,以加速AMP-AD
在新药发现方面取得进展。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,作为一个
中间表型,用于在联合体中产生的丰富组学数据。通过分析样本
通过建立一个连接基因型的图谱,
AD的代谢组学特征,我们希望提供有关AD的机制和亚类的生化见解。
疾病总之,ADMC将提供一个使能代谢互连框架,以加速
AMP-AD治疗进展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Rima F Kaddurah-Daouk其他文献
Rima F Kaddurah-Daouk的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Rima F Kaddurah-Daouk', 18)}}的其他基金
Metabolomic Signatures for Disease Sub-classification and Target Prioritization in AMP-AD
AMP-AD 中疾病亚分类和目标优先级的代谢组学特征
- 批准号:
10084547 - 财政年份:2020
- 资助金额:
$ 150.13万 - 项目类别:
Project 3 - Mechanistic studies on role of gut microbiome in models for Alzheimer's disease
项目 3 - 肠道微生物组在阿尔茨海默病模型中作用的机制研究
- 批准号:
9795005 - 财政年份:2019
- 资助金额:
$ 150.13万 - 项目类别:
Project 3 - Mechanistic studies on role of gut microbiome in models for Alzheimer's disease
项目 3 - 肠道微生物组在阿尔茨海默病模型中作用的机制研究
- 批准号:
10017880 - 财政年份:2019
- 资助金额:
$ 150.13万 - 项目类别:
Project 2 - Influence of controlled diets on gut microbiome, metabolome and cognitive function
项目 2 - 控制饮食对肠道微生物组、代谢组和认知功能的影响
- 批准号:
9795004 - 财政年份:2019
- 资助金额:
$ 150.13万 - 项目类别:
Project 2 - Influence of controlled diets on gut microbiome, metabolome and cognitive function
项目 2 - 控制饮食对肠道微生物组、代谢组和认知功能的影响
- 批准号:
10017878 - 财政年份:2019
- 资助金额:
$ 150.13万 - 项目类别:
Project 1 - Changes in Gut Microbiome and related Metabolome Across Trajectory of Alzheimer's Disease
项目 1 - 阿尔茨海默氏病轨迹中肠道微生物组和相关代谢组的变化
- 批准号:
10017875 - 财政年份:2019
- 资助金额:
$ 150.13万 - 项目类别: