A multiscale investigation of the living human brain

对活人大脑的多尺度研究

基本信息

批准号：
10260466
负责人：
ALEXANDER W CHARNEY
金额：
$ 68.43万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10260466
关键词：
Address Age Alzheimer&apos s disease related dementia Autopsy Bilateral Biology Biopsy Brain Cells Cessation of life Cohort Analysis Communities Data Data Analyses Data Set Deep Brain Stimulation Funding Gender Generations Genome Genomics Genotype Goals Human Individual Investigation Knowledge Medical History Modernization Molecular Molecular Biology Molecular Profiling Multiomic Data Neurobiology Neurocognitive Output Participant Pathogenesis Phenotype Play Prefrontal Cortex Procedures Process Proteome Proteomics Quality Control Resolution Resources Role Sampling Site Specimen Structure Surveys Tissues Uncertainty Work brain tissue case control cell type cohort experimental study genome-wide human subject innovation insight lipidome lipidomics metabolome metabolomics molecular modeling multimodality multiple omics neuroimaging neuropsychiatry single-cell RNA sequencing trait transcriptome transcriptome sequencing transcriptomics virtual

项目摘要

ABSTRACT Molecular investigations of Alzheimer’s disease and related dementias over the past decade have largely relied on postmortem specimens due to the inaccessibility of the brain in living people. At least two serious limitations are inherent to this framework. First, the molecular impact of death and the preceding agonal process on the human brain are unknown. This uncertainty looms over the field as a potential confounder of virtually all modern neurobiological studies of Alzheimer’s disease and related dementias in humans. Second, profiling the brain postmortem decouples molecular biology from deep neuropsychiatric assessment and neuroimaging. As a result, a holistic narrative of how molecular biology influences brain structure and functions dysregulated in Alzheimer’s disease and related dementias has failed to emerge. These serious limitations could be addressed by the ability to molecularly profile the brain in living people. Here, we address these serious limitations through the Living Brain Project, wherein we perform comprehensive multiomic molecular profiling of living and postmortem human brain tissue. The primary innovation of the LBP is a safe, scalable procedure for sampling the dorsolateral prefrontal cortex (DLPFC) in living people. We will profile the genome, transcriptome (bulk and single-cell), proteome, metabolome and lipidome in over 500 living and postmortem human subjects. Analyses of this data will identify molecular signatures differentiating the living and postmortem states. We will harness these insights to determine the extent to which they have confounded postmortem studies of Alzheimer’s disease and related dementias. Finally, we will integrate these multiomics datasets with neuroimaging and neurocognitive assessments from the same individuals. To our knowledge, the proposed experiments and analyses will comprise (1) the largest molecular study of the living human brain, (2) the largest molecular comparison of living and postmortem human brain tissues, and (3) the largest effort pairing multiomic molecular profiles of the brain with neuroimaging and deep neurocognitive phenotyping from the same living individuals. We anticipate fundamental advances in knowledge of human brain biology and the pathogenesis of Alzheimer’s disease and related dementias will be made by making this rich dataset freely available to scientific community.

抽象的在过去的十年中对阿尔茨海默氏病和相关痴呆症的分子研究在很大程度上依赖于验尸标本，这是由于大脑在活人中的无法访问。至少有两个严重的限制继承在此框架上。首先，死亡的分子影响和先前的激动过程对人脑的影响尚不清楚。这种不确定性在该领域的潜在混杂因素即实际上所有现代神经生物学研究的潜在混杂因素，对人类的所有现代神经生物学研究和相关痴呆症。其次，分析大脑后验尸将分子生物学与深度神经精神病学评估和神经成像相关。结果，关于分子生物学如何影响大脑结构和功能在阿尔茨海默氏病和相关痴呆症中失调的整体叙述未能出现。这些严重的局限性可以通过分子在活人中介绍大脑的能力来解决。在这里，我们通过活脑项目解决了这些严重的局限性，其中我们对生活和尸体后人脑组织进行全面的多种分子分析。 LBP的主要创新是一种安全，可扩展的程序，用于在活人中对背外侧前额叶皮层（DLPFC）进行采样。我们将在500多名生活和验尸人类受试者中介绍基因组，转录组（大量和单细胞），蛋白质组，代谢组和脂肪组。对这些数据的分析将确定与生命状态和验尸状态不同的分子特征。我们将利用这些见解，以确定它们在多大程度上混淆了对阿尔茨海默氏病和相关痴呆症的死后研究。最后，我们将将这些多组学数据集与来自同一个人的神经认知和神经认知评估相结合。据我们所知，提出的实验和分析将完成（1）生命人脑的最大分子研究，（2）生命和后人类脑组织的最大分子比较，以及（3）将大脑的多膜分子曲线与神经模仿和深度神经认知的现象相对的最大努力。我们预计了解人脑生物学以及阿尔茨海默氏病的发病机理和相关痴呆症的发病机理将通过使该丰富的数据集自由地向科学界获得。