Single-cell multi-region transcriptional and epigenomic dissection of VCID.

VCID 的单细胞多区域转录和表观基因组解剖。

• 批准号: 10532050
• 负责人: Myriam Heiman
• 金额: $ 305.85万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532050
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anatomy; Area; Arterial Disorder; Atherosclerosis; Atlases; Autopsy; Basal Ganglia; Biological Markers; Blood Vessels; Brain region; CADASIL; Cardiovascular Diseases; Cell Communication; Cell Nucleus; Cells; Cerebral Amyloid Angiopathy; Cerebral small vessel disease; Cerebrovascular Disorders; Cerebrum; Computer Analysis; Coupled; DNA; Data; Data Set; Dementia; Diagnosis; Disease; Disease Progression; Dissection; Enhancers; Etiology; Gene Expression Regulation; Genes; Genetic; Genetic Models; Genetic Transcription; Health Care Costs; Heart; Heart Diseases; Human; Hypertension; Image; Immune; Impaired cognition; Individual; Joints; Link; Maps; Mediation; Medical; Molecular; Morbidity - disease rate; Nerve Degeneration; Neurons; Occipital lobe; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Prefrontal Cortex; Prevalence; Prevention; Protocols documentation; Public Health; Resolution; Sampling; Severities; Small Nuclear RNA; Sterile coverings; Stroke; Subcortical Infarctions; Subcortical Leukoencephalopathy; Therapeutic; Tissues; Transcription Alteration; Variant; Work; aging brain; aging population; base; cell type; cerebrovascular; cerebrovascular lesion; clinical diagnosis; clinically relevant; computer framework; effective therapy; epigenome; epigenomics; genetic variant; heart disease prevention; hypertensive; imaging study; insight; loved ones; male; mortality; multiple omics; novel; novel therapeutics; putamen; sex; success; therapeutic development; trait; transcriptome sequencing; transcriptomics; vascular cognitive impairment and dementia; white matter

Abstract Alzheimer’s disease (AD) and AD-related dementias (ADRDs) are major drivers of mortality, morbidity, and health care costs for patients and their loved ones, due to the aging population, lack of predictive diagnosis, and lack of effective treatments or prevention. Vascular contributions to cognitive impairment and dementia (VCIDs) are key contributors to AD and ADRDs and manifest through diverse cerebrovascular lesions, including atherosclerosis, microinfarcts, and small vessel strokes. VCIDs include cerebral small vessel disease (CSVD), cerebral amyloid angiopathy (CAA), and a monogenic familial form of CSVD (CADASIL, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). Understanding the mechanisms and drivers of VCID will enable new biomarkers and therapeutics, similar to the success of addressing cardiovascular disease and hypertension in heart disease. To understand the cellular mechanisms underlying VCID across brain regions, cell types, pathology, and molecular pathways, we perform high- resolution profiling of epigenomic and transcriptional alterations in post-mortem CNS samples from both sporadic and genetic VCID patients. Aim 1: We profile single-nucleus RNA-sequencing (snRNA-seq) and DNA accessibility (snATAC-seq) to create a transcriptional and epigenomic atlas of VCID across diagnoses, brain regions, cell types, sexes, and individuals. Aim 2: We create an atlas of SVD-associated changes in genes, modules, pathways, and cell-cell interactions. Aim 3: We predict candidate driver genes, regulators, and pathways using causality analyses across temporal and genetic models, and we validate our results experimentally using imaging studies. The successful execution of our studies will delineate clinically-relevant VCID biomarkers and therapeutics across sporadic and genetic VCID, enabling us to dissect their common and distinct molecular circuits, across four affected CNS region and all major cell types within them, and capturing an unprecedented level of complexity and enabling rich computational comparisons. The datasets generated and the computational analyses will provide invaluable insights for addressing the pressing medical need of VCIDs, their temporal, region-specific, and cell-type-specific changes, which can help guide new therapeutics.

抽象的 阿尔茨海默氏病（AD）和与AD相关的痴呆症（ADRDS）是死亡率，发病率和 由于人口老龄化，患者及其亲人的医疗保健费用缺乏预测性诊断， 缺乏有效的治疗或预防。对认知障碍和痴呆症的血管贡献 （VCID）是AD和ADRD的关键因素，并通过潜水脑血管病变表现出来， VCID包括脑小血管疾病 （CSVD），脑淀粉样血管病（CAA）和一种单基因家族形式的CSVD（Cadasil，大脑，大脑 常染色体显性动脉炎，具有下皮质肌和白细胞症状）。了解 VCID的机制和驱动因素将实现新的生物标志物和治疗，类似于 解决心脏病中心血管疾病和高血压。了解细胞机制 跨大脑区域，细胞类型，病理和分子途径的基础VCID，我们执行高 两者的表观基因组学和转录改变的分辨率分析 零星和遗传VCID患者。 AIM 1：我们介绍了单核RNA序列（SNRNA-SEQ）和DNA 可访问性（SNATAC-SEQ）在诊断范围内创建VCID的转录和表观基因组地图 区域，细胞类型，性别和个人。 AIM 2：我们创建了与SVD相关基因变化的地图集， 目标3：我们预测候选驾驶员基因，监管机构和 使用跨临时和遗传模型的偶然性分析的途径，我们验证我们的结果 实验使用成像研究。我们的研究的成功执行将描述与临床相关的 VCID生物标志物和遍布零星和遗传VCID的疗法，使我们能够剖析其共同点 以及在其中四个受影响的中枢神经系统区域及其所有主要细胞类型的不同分子电路，以及 捕获前所未有的复杂性水平并实现丰富的计算比较。数据集 生成的，计算分析将为解决紧迫的医疗提供宝贵的见解 需要VCID，其临时，特定区域和细胞类型的更改，这可以帮助指导新 疗法。