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

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

展开

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.

项目摘要/摘要痴呆症遭受了全球超过5500万人的困扰。人口老龄化，没有有效的治疗可用时，该数字预计到2050年几乎将其数字化。所有痴呆症的45％占中风的约20％，出现在大多数阿尔茨海默氏病患者中。 CSVD 来自大脑约400英里的氧和营养小动脉的病理学，动脉，静脉和毛细血管；并被认为是认知障碍的最重要的血管贡献者和痴呆（VCID）。 CSVD病理，例如小动脉粥样硬化和微作用，暗中发展为奇怪的脑血流，损害血脑屏障，并触发神经炎症。最近的单核测序技术的发展已经开始阐明基本分子和人类神经系统疾病的基础过程。他们已经揭示了有选择性的脆弱单元种群，跨疾病阶段的转录功能障碍以及遗传风险变异的机制告知新的研究领域和治疗目标。然而，单核研究主要失去了人类大脑血管细胞未知原因，使我们对CSVD滞后的理解。为了应对这一挑战，我们发明的血管分离和核提取进行测序（藤本式）以有效捕获人脑来自冷冻后大脑的血管细胞类型，用于单核分析。在这里，我们将结合葡萄树具有多模式的单核RNA和ATAC测序，以产生〜190万个血管地图集早期，中期和后期CSVD以及年龄匹配的认知正常对照。样本来自一个特殊组织的CSVD套件是191个验尸后中部回，分水岭，优先于MRI和神经拖拉机，宗教秩序研究，记忆和衰老项目（Rosmap）。样品没有任何混杂的非血管神经退行性病理学，并用人口统计学注释基因组，病理和纵向认知数据将分子读数与表型联系起来。那我们会的将葡萄树与多模式的单核RNA-和ATAC-Sequer（SnRNA/ATAC-SEQ）结合在一起产生CSVD（A1）的第一个血管图谱；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修改的，洞察力这里揭示的可能对理解和最终治疗VCID和混合病理痴呆症至关重要。