Integrative translational discovery of vascular risk factors in aging and dementia

衰老和痴呆血管危险因素的综合转化发现

• 批准号: 9421402
• 负责人: GUOJUN BU
• 金额: $ 357.77万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9421402
• 关键词: Address; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Autopsy; Biochemical; Biological; Biological Models; Blood Vessels; Brain; Brain Diseases; Cells; ChIP-seq; Chromatin; Clinic; Clinical; Cognitive; Complex; Data; Data Set; Dementia; Disease; Drug Targeting; Elderly; Environmental Risk Factor; Epigenetic Process; Etiology; Event; Funding; Gene Proteins; Generations; Genes; Genetic; Genetic Risk; Genetic Transcription; Genotype; Goals; Gonadal Steroid Hormones; Grant; Heterogeneity; Human; Inflammatory; Knowledge; Lead; Measurement; Measures; Medicine; Meta-Analysis; Methylation; Modeling; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Outcome; Parents; Participant; Pathologic; Pathway Analysis; Pathway interactions; Patients; Phenotype; Plasma; Prospective cohort; Protein Isoforms; RNA Sequences; Risk; Risk Factors; Role; Sampling; Science; Senile Plaques; Testing; Tissue Sample; Tissues; United States National Institutes of Health; apolipoprotein E-3; biomarker discovery; cohort; data sharing; drug discovery; endophenotype; functional genomics; functional outcomes; genome-wide; human data; lipid metabolism; metabolome; metabolomics; methylome; mouse model; network models; neuroimaging; neuropathology; new therapeutic target; novel; parent grant; programs; proteostasis; response; sex; targeted biomarker; tau Proteins; transcriptome

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia characterized by brain accumulation of senile plaques and neurofibrillary tangles. AD risk is likely influenced by a multitude of genetic and environmental risk factors and their complex interplay, which subsequently lead to cascades of downstream pathophysiologic events that include but are not limited to aberrant proteostasis and lipid metabolism, as well as inflammatory, vascular, and oxidative mechanisms. The array of risk factors that lead to AD and their downstream influences are likely to be heterogeneous amongst AD patients, which complicates the search for drug targets, biomarkers and their potential downstream beneficial use in any given AD patient. For this reason, drug target and biomarker discovery efforts in AD have to focus on identification of both molecular mechanisms that are commonly perturbed in AD patients, as well as those mechanisms that may underlie heterogeneity in AD. To overcome this massive challenge, team-science efforts, including the NIH initiatives, Accelerating Medicines Partnership-AD (AMP-AD) and Molecular Mechanisms of the Vascular Etiology of AD (M2OVE-AD) Consortia, have launched large-scale generation and analyses of multi-omics data from well- phenotyped human cohorts and model systems. These consortia aim to integrate multi-omics and clinical endophenotype data to build a model(s) of AD that captures these common and heterogeneous pathomechanisms. Our teams are leading participants of both AMP-AD and M2OVE-AD. The initial findings from these consortia reveal concerted changes in networks of expressed genes and proteins in AD subjects and model systems, with biological significance. Despite this progress and wide and immediate sharing of the data generated by these programs, significant gaps remain in the available –omics data, and the ability to integrate, harmonize and annotate these datasets. Our proposal is in response to the RFA-AG-17-054, which aims to close these gaps. In this proposal, we maintain the overall objective of our parent funded M2OVE-AD project (RF1 AG51504), which is to determine APOE- and sex-dependent effects, and uncover novel genes and pathways that influence vascular risk in aging, AD and other dementias. Our specific aims are: 1. Integrative functional genomic analysis of human brains to discover novel pathways in AD. 2. Integrative functional genomic analysis in a prospective cohort to validate and discover AD pathways. 3. Investigate the impact of APOE genotype and sex on transcriptional networks and the metabolome in model systems. 4. Perform single-cell profiling to annotate the transcriptome data from AMP-AD and M2OVE-AD. These studies will add key epigenetic data (H3K9Ac and RRBS methylome) to the human and transcriptome and metabolomics data to the mouse cohorts, generate human and mouse single cell transcriptome data, and perform integrative network analyses. We expect this proposal to fill key gaps in knowledge and further enhance the AMP-AD and M2OVE-AD initiatives in their drug and biomarker discovery goals.

项目总结/文摘