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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：
10002163
负责人：
Rima F Kaddurah-Daouk
金额：
$ 160.48万
依托单位：
DUKE UNIVERSITY
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：
https://reporter.nih.gov/project-details/10002163
关键词：
Address Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapeutic Amines Animals Antidepressive Agents Atlases Atrophic Bile Acids Binding Biochemical Biochemical Pathway Biological Markers Biological Models Blood specimen Brain Brain Diseases Brain imaging Branched-Chain Amino Acids Cardiovascular Diseases Chemicals Cholesterol Classification Clinical Clinical Trials Cognition Cognitive Communities Data Databases Development Diabetes Mellitus Disease Drug Targeting Drug usage Early Intervention Enzymes Failure Fatty Liver Fluorouracil Foundations Framingham Heart Study Functional disorder Gene Expression Genes Genetic Genetic Variation Genome Genotype Glucose Glutamates Goals Heterogeneity Human Impaired cognition Knowledge Lead Lecithin Life Style Link Lipids Liver Liver diseases Malignant Neoplasms Measures Medical Metabolic Metabolic Pathway Metabolism Molecular Monitor Network-based Neurotransmitters Pathogenesis Pathway interactions Patients Peripheral Phagocytosis Pharmaceutical Preparations Phase Phenotype Prevention Proxy Regulation Research Risk Risk Factors Role Sampling Sex Differences Signal Transduction Signaling Molecule Sphingomyelins Stratification Structure Symptoms Time Translations Tryptophan Tyrosine Validation Vertebral column biomarker development brain health clinical phenotype clinical subtypes cohort cytotoxic disease phenotype disorder subtype drug development drug discovery gut microbiome human data immune function insight metabolic phenotype metabolomics molecular scale network models neuroimaging new therapeutic target novel novel therapeutics pre-clinical precision medicine protein expression research clinical testing sex tool treatment 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.

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