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

• 批准号: 10011923
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011923
• 关键词: ATAC-seq; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' 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; 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; religious order study; response; sex; single-cell RNA sequencing; social; tau Proteins; therapeutic development; therapeutic target; trait; transcriptomics; vascular cognitive impairment and dementia; whole genome

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，具有巨大的个人，社会和经济负担，影响全球超过4700万人，迄今尚未治愈。痴呆的主要类型包括阿尔茨海默氏病（AD）、路易体痴呆（LBD）和额颞叶痴呆（FTD），其显示出不同的和重叠的病理学、神经学和细胞特征，但其详细的分子特征仍然未被表征。在这里，我们系统地分析了AD，LBD，FTD和健康老龄化的分子特征，在单细胞水平上，跨特征，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，表观基因组和转录谱，在单细胞（sc）水平上使用scRNA-seq和scATAC-seq在宗教秩序研究和记忆与衰老项目（ROS MAP）队列的768个死后大脑样本中生成了总计约150万个全基因组图谱。我们在全基因组测序的遗传变异背景下分析所得数据集，并从丰富的纵向分析和认知评估中分析表型变异，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，途径，细胞类型和大脑区域，以及它们如何在年龄，性别和特征中变化。由此产生的数据集将通过提供详细的治疗靶点以及预测它们起作用的特定条件来帮助指导新疗法的搜索。