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个人，社会和财务燃烧的主要公共卫生问题，影响了全球超过4700万人，但迄今为止尚无治愈。痴呆症的主要类型包括阿尔茨海默氏病（AD），Lewy身体痴呆症（LBD）和额颞痴呆（FTD），它们显示出明显的和重叠的病理，神经学和细胞特征，但其详细的分子特征仍然没有任何特征。在这里，我们系统地介绍了AD，LBD，FTD和健康衰老的分子特征，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。我们使用遗传，表观基因组和转录曲线，在768个宗教秩序研究和记忆和衰老项目（ROS Project（ROS ROS MAP））中，使用SCRNA-SEQ和SCATAC-SEQ在单细胞（SC）水平上产生约150万个全基因组图的图。我们在全基因组测序中分析了所得数据集，以及从丰富的纵向分析和认知评估中的表型变化，使我们能够发现基因，控制区，途径，途径，细胞类型和大脑区域在AD和ADRD中起着因果关系在AD和ADRD中扮演因果关系，以及它们在各种年龄跨年龄，性别，性别，性别，性别，性别，属性和特征。最终的数据集将通过提供详细的治疗靶标以及预测采取行动的特定条件来帮助指导寻找新疗法的搜索。