Single-cell epigenomic and trancriptional dissection of sex-specific differences in Alzheimer’s Disease

阿尔茨海默病性别特异性差异的单细胞表观基因组和转录解析

基本信息

批准号：
10495202
负责人：
Manolis Kellis
金额：
$ 108.51万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10495202
关键词：
Address Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Autopsy Biological Assay Blood - brain barrier anatomy Brain Brain region Categories Cells Cerebrovascular system Computing Methodologies DNA Data Data Set Dementia Development Disease Dissection Electronic Health Record Enhancers Family Female Foundations Functional disorder Gene Expression Profile Genes Genetic Genetic Risk Genetic Transcription Genetic study Genomics Genotype Germ Cells Healthcare Heterogeneity Hi-C Hippocampus (Brain)Homeostasis Hormonal Human Image Impaired cognition Individual Intervention Lead Libido Life Light Link Lipids Maps Memory Loss Metabolic Modeling Molecular Molecular Genetics Molecular Mechanisms of Action Mus Mutation Neurodegenerative Disorders Nucleic Acid Regulatory Sequences Pathway interactions Patients Phenotype Physiological Regulatory Element Resolution Resources Risk Sampling Severities Severity of illness Sex Differences Synaptic plasticity System Testing Transcription Alteration Untranslated RNA Validation Variant XCL1 gene age related base brain cell causal variant cell type cohort epigenomics frontal lobe genetic signature in vitro Model induced pluripotent stem cell male mind control mouse model novel therapeutics personalized medicine personalized therapeutic promoter risk variant sex single-cell RNA sequencing therapeutic development

项目摘要

Abstract Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that leads to dramatic effects on the affected individuals and their families. While the characterization of the genetic contribution to AD and underlying molecular mechanisms have advanced the understanding of the disease in recent years, studies show that sex differences account for much of the observed differences in risk, progression, and severity across individuals. Here, we directly dissect the contribution of sex-specific variation down to the region- specific and cell-type-specific molecular basis by systematic profiling, computational integration, and experimental validation of the transcriptional, epigenomic, and genetic signatures across individuals, brain regions, and cell types. In Aim 1, we use genetic, epigenomic, and transcriptional profiles, generating millions of single-cell (sc) level maps using scRNA-seq and scATAC-seq across human and mouse samples of varying ages and genetic risk status. In Aim 2, we analyze the resulting datasets in the context of known AD genetic risk variation and underlying molecular mechanisms, enabling us to discover and converge variants, regulatory regions, genes, pathways, cell types, and brain regions to functional, causal mechanisms that drive sex-related differences. In Aim 3, we use our well-established mouse and iPSC models to test our predicted mechanisms with both high-throughput and cell-type specific assays. The resulting datasets, computational predictions, and experimentally-supported mechanisms will shed light on the sex-related differences of AD and will help deepen our understanding the disease in general as we develop more personalized therapeutic approaches in treating AD.

抽象的阿尔茨海默氏病（AD）是一种毁灭性的神经退行性疾病，导致对影响个人及其家人。而遗传贡献对AD的表征和近年来，潜在的分子机制已经提高了对疾病的理解。表明性别差异解释了大部分观察到的风险，进展和严重性差异跨个人。在这里，我们直接剖析了性别特异性变异对区域的贡献 - 特定和细胞类型的特异性分子基础，通过系统分析，计算整合和对个体的转录，表观基因组和遗传学的实验验证，大脑区域和细胞类型。在AIM 1中，我们使用遗传，表观基因组和转录轮廓，产生数百万使用SCRNA-SEQ和SCATAC-SEQ的单细胞（SC）级别图的人类和小鼠样品的不同年龄和遗传风险状况。在AIM 2中，我们在已知的AD遗传的背景下分析了所得数据集风险变化和潜在的分子机制，使我们能够发现和收敛变体，调节性区域，基因，途径，细胞类型和大脑区域促进与性别相关的功能性，因果机制差异。在AIM 3中，我们使用良好的鼠标和IPSC模型来测试我们的预测机制具有高通量和细胞类型的特定测定法。结果数据集，计算预测和实验支持的机制将阐明与性别相关的AD差异，并有助于加深当我们开发更多个性化的治疗方法时，我们总体上了解疾病广告。