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.

项目摘要 阿尔茨海默氏病（AD）是一种多因素疾病，具有复杂的病因，性别对广告的影响 在临床和神经病理发展过程中。基础和临床研究支持性别 对AD发病机理和进展的特定贡献。已鉴定出载脂蛋白E4（APOE4）等位基因 作为主要的遗传危险因素。性别和APOE4等位基因在AD风险中的相互作用，临床表现， 在各种临床试验中，病理过程以及治疗反应能力已被探讨。 但是，AD中性别二态性的分子机制以及APOE4如何分层性别差异 在广告中仍然难以捉摸。与系统生物学方法同时的多摩学数据为不提供新的途径 仅剖析AD的性别和APOE分层的分子机制，但也会发展出性别特异性的诊断和 AD的治疗干预措施。单细胞转录组数据集以及散装组织的细胞反卷积 转录组可深入了解大脑区域特异性和细胞类型对性别的影响 AD中的二态性。在此应用中，我们建议开发广告的性别和特定于APOE的网络模型 对大规模批量和单个多摩变数据进行集成的多尺度网络分析。尤其， 我们将在AD中开发第一个单核多词数据的队列（同时进行RNA测序和 每个单元的ATAC序列）可能意味着通过性别和APOE基因型完全分层。我们将 还将在AD中策划现有的单核RNA-Seq数据集并与我们自己的单细胞多词相结合 数据集以识别AD的性别特异性遗传变异和分子特征（AIM 1）。我们将表演 整合网络分析以研究大脑区域AD中性别和APOE基因型之间的相互作用 以及单细胞级别，并从网络模型性别和特定于AD的网络驱动程序中识别（AIM） 2）。然后，我们将通过通过药物候选者的潜在疗法来通过药物候选者进行预测 大型电子病历（EMR）数据库的虚拟临床试验（AIM 3）。最后，我们将在功能上 通过遗传操纵（上或 基因表达的下调）以及与鉴定药物的药物扰动 通过使用相关的人IPSC培养系统和AD小鼠模型进行虚拟药物筛查（AIM 4）。这 该项目的发现将指导未来的有效性和APOE分层的干预措施 广告。