Single-cell transcriptional and epigenomic dissection of Alzheimer's Disease and Related Dementias

阿尔茨海默病和相关痴呆症的单细胞转录和表观基因组解剖

基本信息

批准号：
9791035
负责人：
Manolis Kellis
金额：
$ 134.54万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9791035
关键词：
ATAC-seq Address Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid beta-Protein Autopsy Bayesian Method Biological Blood Vessels Brain Brain region Cells Classification Cleaved cell Clinical Clinical Management Clinical Trials Code Cognition Cognitive DNA DNA-Binding Proteins Data Data Set Defect Dementia Deposition Development Diagnostic Dissection Distal Elderly Enhancers Evaluation Financial Hardship Frontotemporal Dementia Gene Expression Profiling Genes Genetic Genetic Transcription Genetic Variation Hippocampus (Brain)Individual Injury Lewy Bodies Lewy Body Dementia Link Maps Mediation Memory Molecular Molecular Profiling Mutation Neurofibrillary Tangles Neurologic Nucleic Acid Regulatory Sequences Pathologic Pathway interactions Personality Phenotype Play Prefrontal Cortex Public Health Religion and Spirituality Resources Role Sampling Senile Plaques Severities Severity of illness Social Behavior Stroke Techniques Technology Therapeutic Intervention Transact Transposase Untranslated RNA Variant alpha synuclein base cell type cohort differential expression epigenomics extracellular gene discovery genetic information genome sequencing genome wide association study genome-wide healthy aging insight new therapeutic target novel therapeutics prognostic rare variant response sex single-cell RNA sequencing social tau Proteins therapeutic development therapeutic target trait transcriptomics vascular cognitive impairment and dementia whole genome

项目摘要

Dementia is a major public health problem with substantial personal, social, and financial burden, affecting more than 47 million people worldwide, with no cure to date. The major types of dementia include Alzheimer’s disease (AD), Lewy Body dementia (LBD), and frontotemporal dementia (FTD), which show distinct and overlapping pathological, neurological, and cellular signatures, but their detailed molecular signatures remain uncharacterized. Here, we systematically profile the molecular signatures of AD, LBD, FTD, and healthy aging, at the single-cell level, across traits, individuals, brain regions, cell types, age, sex, and disease severity. We use genetic, epigenomic, and transcriptional profiles, generating a total of ~1.5 million genome-wide maps at the single-cell (sc) level using scRNA-seq and scATAC-seq across 768 post-mortem brain samples from the Religious Order Study and Memory and Aging Project (ROS MAP) cohorts. We analyze the resulting datasets in the context of genetic variation from whole-genome sequencing, and phenotypic variation from rich longitudinal profiling and cognitive evaluations, enabling us to discover genes, control regions, pathways, cell types, and brain regions playing causal roles in AD and ADRD, and how they vary across age, sex, and traits. The resulting datasets will help guide the search for new therapeutics, by providing detailed therapeutic targets, and the specific conditions where they are predicted to act.

痴呆症是一个重大的公共卫生问题，给个人、社会和经济带来沉重负担，影响着全世界超过 4700 万人，迄今为止，痴呆症的主要类型包括阿尔茨海默病 (AD)、路易体痴呆 (LBD)、和额颞叶痴呆 (FTD)，它们表现出独特且重叠的病理、神经和细胞特征，但其详细的分子特征仍未表征。在这里，我们系统地描述了 AD、LBD、FTD 和健康的分子特征。我们使用遗传、表观基因组和转录图谱，在单细胞水平上，跨性状、个体、大脑区域、细胞类型、年龄、性别和疾病严重程度，生成了总共约 150 万个全基因组图谱。我们使用 scRNA-seq 和 scATAC-seq 对来自宗教秩序研究和记忆与衰老项目 (ROS MAP) 队列的 768 个死后大脑样本进行单细胞 (sc) 水平分析。全基因组测序的遗传变异，以及丰富的纵向分析和认知评估的表型变异，使我们能够发现在 AD 和 ADRD 中发挥因果作用的基因、控制区域、通路、细胞类型和大脑区域，以及它们如何随年龄变化、性别和特征。由此产生的数据集将通过提供详细的治疗目标以及预测它们发挥作用的具体条件来帮助指导新疗法的搜索。