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Sex-specific Molecular Profiling to Understand Pathology and Identify Causal Genes and Drug Targets for Alzheimer's Disease

通过性别特异性分子分析来了解阿尔茨海默病的病理学并识别致病基因和药物靶点

基本信息

批准号：
10300830
负责人：
YunJu Sung
金额：
$ 274.07万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10300830
关键词：
Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-Protein Astrocytes Automobile Driving Biological Biological Markers Biology Brain CRISPR/Cas technology Cells Cerebrospinal Fluid Characteristics Clinic Clinical Collection Communities DNA Methylation Data Diagnostic Disease Disease Progression Drug Targeting Ethnic Origin Etiology FDA approved Female Functional disorder Gene Expression Gene Expression Regulation Gene Proteins Gene Targeting Genes Genetic Genetic Markers Genetic Variation Genomics Genotype-Tissue Expression Project Germ Cells Goals Human Induced pluripotent stem cell derived neurons Inherited Innate Immune Response Interdisciplinary Study Knowledge Portal Life Expectancy Lysosomes Maps Memory Mendelian randomization Methylation Microglia Molecular Molecular Profiling Multiomic Data Nerve Degeneration Neurons Participant Pathogenicity Pathology Pathway interactions Pharmaceutical Preparations Plasma Proteomics Quantitative Trait Loci Race Reporting Reproducibility Request for Applications Research Resources Role Sampling Series Sex Differences Sex Differentiation TREM2 gene Technology Therapeutic Tissues United States National Institutes of Health Universities Washington Woman aging brain causal variant clinically translatable connectome data sharing disorder risk epigenomics genetic architecture genetic variant genome wide association study genome-wide high dimensionality high risk individualized medicine individualized prevention induced pluripotent stem cell insight lipidomics male metabolomics molecular marker multiple omics neuroimaging new therapeutic target novel predictive modeling preventive intervention proteomic signature response risk variant sex specific biomarkers stem cell model tau Proteins transcriptomics

项目摘要

Abstract Alzheimer's disease (AD) is a highly heterogeneous multifactorial disease. Genetic influences on AD are strong as shown by several pathogenic genes and over 50 AD loci identified through genome-wide association studies (GWAS). There are also clear sex differences in AD risk and progression. Women are at a higher risk of developing AD and present faster progression. A recent GTEx study also highlights sex differences in the genetic regulation of gene expression. Despite these established sex differences, sex-specific molecular findings in AD are still limited. The objective of this study is therefore to generate detailed sex-specific multi- tissue molecular profiles of AD and decipher the genetic architecture that underlies AD. We propose to identify sex-specific functional mechanisms underlying the genetic architecture of AD. We will generate multiple layers of -omics data, including DNA methylation, gene expression, proteomics, metabolomics, and lipidomics, from several large and well characterized studies. A series of well-powered sex-specific omics characterization across multiple tissues can help identify novel drug targets and provide critical insights for clinically translatable interventions for prevention and treatment. We will then map additional GWAS loci by performing sex-specific multi-omic quantitative trait loci and co-localization for each -omic layers. We will identify the causal genes, proteins, and additional -omic analytes by performing Mendelian randomization. Analyzing such omics data will elucidate a causal path from sex-specific genetic variation to AD risk, onset and progression. The human multi- omic data will finally be combined with induced pluripotent stem cell (iPSC) models to identify novel sex- specific FDA-approved therapeutics. We have assembled a very productive and interdisciplinary research team with expertise in all the aspect of the proposal. All aims in this proposal will be conducted and reported in compliance with NIH guidance on scientific rigor and reproducibility. Our preliminary data already identified several genes and proteins that are associated with AD risk and cerebrospinal fluid biomarkers in a sex- specific manner. All the raw data will be shared via NIA-approved mechanism (including AD Knowledge Portal, NIAGADS). This rich resource will benefit the field for additional analyses beyond the ones proposed here.

摘要