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Systems Genetics Analysis of Sex Differences in Alzheimer's Disease

阿尔茨海默病性别差异的系统遗传学分析

基本信息

批准号：
10300717
负责人：
Oscar Harari
金额：
$ 128.29万
依托单位：
JACKSON LABORATORY
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：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10300717
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Apolipoprotein E Atlases Behavioral Biological Biological Models Brain Brain region Cells Clinical Clinical Data Clinical Trials Cognitive Consensus Data Data Set Development Disease Disease Progression Etiology Female Gene Expression Genes Genetic Genetic Markers Genetic Variation Genomic Segment Genomics Genotype Grain Heritability Heterogeneity Human Human Genetics Impaired cognition Individual Inherited Institution Intervention Libido Mediating Methodology Modeling Molecular Mus Mutation Neurobehavioral Manifestations Neurobiology Nuclear RNA Outcome Pathogenesis Pathway interactions Population Precision therapeutics Presenile Alzheimer Dementia Quantitative Trait Loci Research Resolution Resources Risk Role Sex Differences Specificity Symptoms System Systems Biology Technology The Jackson Laboratory Therapeutic Validation Variant Woman Work base behavioral phenotyping bioinformatics tool cell type cohort differential expression disease heterogeneity familial Alzheimer disease genetic analysis genetic approach genetic architecture genetic resource genomic data genomic tools high risk human data human model human tissue humanized mouse improved in vivo insight interdisciplinary collaboration male metabolic phenotype mouse genetics mouse model multidisciplinary neuropathology novel personalized approach personalized intervention personalized therapeutic presenilin-1 presenilin-2 resilience response sex transcriptome sequencing treatment response

项目摘要

PROJECT SUMMARY Our proposed research aims to identify sex-specific genetic drivers of neuropathologic, cognitive, and metabolic phenotypes of Alzheimer’s disease by integrating longitudinal behavioral and molecular data from AD mice with genetic, genomic and clinical data from human cohorts. We will leverage a newly generated mouse population that incorporates high-risk familial AD (FAD) mutations on a genetically diverse background (BXD panel) to identify modifiers that contribute to AD resilience in this ‘humanized’ mouse population. In parallel, we will incorporate cutting-edge single-cell omic approachs to generate a molecular atlas of human brains from carriers of FAD mutations (in APP, PSEN1 and PSEN2) and non-carriers with sporadic AD. By combining and validating analyses in both mouse and human datasets, we expect to find molecular candidates that robustly contribute to sex-specific variation in symptoms of AD. We will further validate these candidates using unparalleled in vivo mouse technology to not only empircally assess their role in sex-specific mechanisms of disease, but also to evaluate sex X genotype X treatment interactions in a subset of candidates (i.e., Apoe) to inform more personalized therapeutic approaches. The approach we propose benefits from the enhanced discovery power and value of existing human genetics resources and novel, precision AD mouse models across multiple institutions to investigate the mechanisms of sex differences in AD.

项目总结