Dissect the interplay between sex and APOE at the single cell level to uncover novel pathways, targets and therapeutics for Alzheimer's disease

在单细胞水平上剖析性别与 APOE 之间的相互作用，以揭示阿尔茨海默病的新途径、靶点和治疗方法

• 批准号: 10300781
• 负责人: Dongming Cai
• 金额: $ 364.19万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10300781
• 关键词: 3-Dimensional; ATAC-seq; Algorithms; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Apolipoprotein E; Basic Science; Biology; Brain; Brain region; Cell Culture Techniques; Cell Nucleus; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Coculture Techniques; Cognitive deficits; Complex; Computerized Medical Record; Data; Data Set; Databases; Development; Diagnostic; Disease; Essential Genes; Etiology; FDA approved; Future; Gene Expression; Genes; Genetic; Genotype; Hippocampus (Brain); Human; Injections; Intervention; Methods; Molecular; Molecular Profiling; Multiomic Data; Mus; Pathogenesis; Pathologic Processes; Pathology; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Risk; Structure; Subgroup; System; Systems Biology; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Tissues; Up-Regulation; Validation; Variant; XCL1 gene; apolipoprotein E-4; brain cell; causal variant; cell type; cohort; drug candidate; drug use screening; gene repression; genetic manipulation; genetic risk factor; genetic variant; human disease; induced pluripotent stem cell; insight; mouse model; multiple drug use; multiple omics; network models; neuroimaging; novel; research study; sex; sexual dimorphism; single-cell RNA sequencing; targeted treatment; transcriptome; transcriptome sequencing; transcriptomics; virtual; virtual clinical trial

Project Summary Alzheimer’s disease (AD) is a multifactorial disorder with complex etiologies and the impact of sex on AD varies over the course of clinical and neuropathological development. Basic and clinical research studies support sex- specific contributions to AD pathogenesis and progression. Apolipoprotein E4 (APOE4) allele has been identified as a primary genetic risk factor. The interplay between sex and APOE4 allele in AD risks, clinical manifestation, pathological processes as well as treatment responsiveness in various clinical trials have been explored. However, the molecular mechanisms underlying sex dimorphism in AD and how APOE4 stratifies sex divergence in AD remain elusive. Multi-omics data in tandem with systems biology approaches offer a new avenue to not only dissect sex- and APOE-stratified molecular mechanisms of AD but also develop sex-specific diagnostic and therapeutic interventions for AD. Single-cell transcriptomic datasets as well as cell deconvolution of bulk tissue transcriptomes provide in-depth insights into brain region-specific and cell-type specific impact on sex dimorphism in AD. In this application, we propose to develop sex- and APOE-specific network models of AD by performing integrative multiscale network analysis of large-scale bulk and single multi-omics data. In particular, we will develop the first cohort of single nucleus multi-omics data in AD (simultaneous RNA-sequencing and ATAC-sequencing of each single cell) that can meaningfully be stratified by sex and APOE genotype. We will also curate existing single nucleus RNA-seq datasets in AD and combine with our own single cell multi-omics dataset to identify sex-specific genetic variants and molecular signatures of AD (Aim 1). We will perform integrative network analysis to investigate the interplay between sex and APOE genotypes in AD at brain-region and single-cell levels and identify from the network models sex- and APOE-specific, network drivers for AD (Aim 2). We will then identify potential therapeutics of selected key drivers with drug candidate prediction through virtual clinical trials of large electronic medical record (EMR) databases (Aim 3). Finally, we will functionally validate the top predicted sex- and APOE-specific molecular network drivers by genetic manipulations (up- or down-regulation of gene expression), as well as pharmacological perturbation with drug candidates identified from virtual drug screening using relevant human iPSC culture systems and AD mouse models (Aim 4). The findings from this project will guide future development of efficacious sex- and APOE-stratified interventions for AD.

项目总结