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Elucidating microvascular contributions to cognitive impairment at single-cell resolution

在单细胞分辨率下阐明微血管对认知障碍的影响

基本信息

批准号：
10656541
负责人：
Andrew Chris Yang
金额：
$ 101.39万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656541
关键词：
ATAC-seq Acceleration Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Anterior Area Arteries Arterioloscleroses Atlases Autopsy Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Brain Diseases Brain Pathology Brain region Cell Density Cell Nucleus Cell physiology Cells Cerebral small vessel disease Cerebrovascular Circulation Chromatin Cognitive Cognitive deficits Complement Data Data Set Dementia Development Disease Disease Progression Endothelium Exhibits Fibroblasts Freezing Frontal gyrus Functional disorder Gene Expression Gene Expression Profile Genes Genetic Risk Genetic Transcription Genomics Heritability Human Impaired cognition Infarction Joints Lesion Link Macrophage Magnetic Resonance Imaging Maps Mediating Memory Messenger RNA Methods Molecular Molecular Profiling Nerve Nerve Degeneration Neuroglia Nutrient Oxygen Pathologic Pathology Pathway interactions Pericytes Persons Phenotype Population Process Quality Control Quantitative Trait Loci Radiology Specialty Regulator Genes Research Resolution Sampling Small Nuclear RNA Stroke T-Lymphocyte Techniques Technology Tissues Variant Vascular Cognitive Impairment aging population arteriole causal variant cell type cerebrovascular density design effective therapy epigenomics insight invention mild cognitive impairment mixed dementia multimodality nervous system disorder neuroinflammation power analysis religious order study risk variant single nucleus RNA-sequencing therapeutic target tractography transcription factor transcriptomics vascular risk factor venule

项目摘要

Project Summary/Abstract Dementia afflicts over 55 million people worldwide. With an aging population and no effective treatments available, this number is projected to nearly triple by 2050. Cerebral small vessel disease (CSVD) causes up to 45% of all dementia, accounts for ~20% of strokes, and appears in most Alzheimer’s disease patients. CSVD arises from pathologies of the brain’s ~400 miles of oxygen and nutrient-delivering small arteries, arterioles, venules, and capillaries; and is recognized as the most important vascular contributor to cognitive impairment and dementia (VCID). CSVD pathologies, such as arteriolosclerosis and microinfarcts, develop insidiously to strangulate cerebral blood flow, compromise the blood-brain barrier, and trigger neuroinflammation. Recent developments in single-nucleus sequencing technologies have begun elucidating fundamental molecular and cellular processes underlying human neurological disease. They have revealed selectively vulnerable cell populations, transcriptional dysfunction across disease stages, and the mechanisms of genetic risk variants to inform new research areas and therapeutic targets. Yet, single-nucleus studies have mostly lost human brain vascular cells unknown reasons, leaving our understanding of CSVD lagging. To address this challenge, we invented Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to efficiently capture human brain vascular cell types from frozen postmortem brains for single-nucleus profiling. Here, we will combine VINE-seq with multimodal single-nucleus RNA and ATAC sequencing to generate a first ~1.9 million vascular atlas of early, mid-, and late-stage CSVD alongside age-matched cognitively normal controls. Samples come from a specially organized CSVD set of 191 postmortem midfrontal gyrus watershed tissue, prioritized via MRI and nerve tractography, from the Religious Order Study and Memory and Aging Project (ROSMAP). Samples exhibit no confounding non-vascular neurodegenerative pathology and are richly annotated with demographic, genomic, pathologic, and longitudinal cognitive data to link molecular readouts to phenotypes. Thus, we will combine VINE-seq with multimodal single-nucleus RNA- and ATAC- sequencing (snRNA/ATAC-seq) to generate a first vascular atlas of CSVD (A1); reveal the molecular signatures of CSVD progression (A2); and determine the causal mechanisms of CSVD genetic risk (A3). As vascular risk factors are modifiable, insights revealed here may be critical to understanding and ultimately treating VCID and mixed pathology dementias.

项目概要/摘要全球有超过 5500 万人患有痴呆症。人口老龄化且无有效治疗方法预计到 2050 年，这一数字将增加近两倍。脑小血管疾病 (CSVD) 会导致占所有痴呆症的 45%，约占中风的 20%，并且出现在大多数阿尔茨海默病患者中。脑血管病源于大脑约 400 英里的输送氧气和营养的小动脉、小动脉的病变，小静脉和毛细血管；并被认为是导致认知障碍的最重要的血管因素和痴呆症（VCID）。脑小血管病（CSVD）病理，如动脉硬化和微梗塞，会潜移默化地发展到抑制脑血流，损害血脑屏障，并引发神经炎症。最近的单核测序技术的发展已经开始阐明基本的分子和人类神经疾病的细胞过程。他们选择性地揭示了脆弱细胞人群、跨疾病阶段的转录功能障碍以及遗传风险变异的机制为新的研究领域和治疗目标提供信息。然而，单核研究大多失去了人类大脑血管细胞的不明原因，使得我们对CSVD的认识滞后。为了应对这一挑战，我们发明血管分离和细胞核提取测序（VINE-seq）以有效捕获人脑来自冷冻死后大脑的血管细胞类型，用于单核分析。这里，我们将结合VINE-seq 通过多模式单核 RNA 和 ATAC 测序，生成第一个约 190 万个血管图谱早期、中期和晚期 CSVD 以及年龄匹配的认知正常对照。样品来自特别组织的 CSVD 集 191 个死后额中回分水岭组织，通过 MRI 和神经束成像，来自宗教秩序研究和记忆与衰老项目 (ROSMAP)。样品没有表现出令人困惑的非血管神经退行性病理学，并且具有丰富的人口统计注释，基因组、病理学和纵向认知数据将分子读数与表型联系起来。这样，我们将将 VINE-seq 与多模式单核 RNA 和 ATAC 测序 (snRNA/ATAC-seq) 相结合生成第一个 CSVD 血管图谱 (A1)；揭示 CSVD 进展的分子特征 (A2)；和确定 CSVD 遗传风险的因果机制 (A3)。由于血管危险因素是可以改变的，见解这里揭示的内容可能对于理解和最终治疗 VCID 和混合病理性痴呆至关重要。