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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.

抽象的由于活人的大脑无法进入，过去十年对阿尔茨海默病和相关痴呆症的分子研究很大程度上依赖于死后标本。该框架至少存在两个严重的局限性。首先，死亡和之前的痛苦过程对人脑的分子影响尚不清楚。这种不确定性笼罩在该领域，成为几乎所有有关人类阿尔茨海默病和相关痴呆症的现代神经生物学研究的潜在混杂因素。其次，对死后大脑进行分析将分子生物学与深层神经精神评估和神经影像学脱钩。因此，关于分子生物学如何影响阿尔茨海默病和相关痴呆症中大脑结构和功能失调的整体叙述尚未出现。这些严重的限制可以通过对活人大脑进行分子分析的能力来解决。在这里，我们通过活脑项目解决这些严重的局限性，其中我们对活体和死后人类脑组织进行全面的多组学分子分析。 LBP 的主要创新是一种安全、可扩展的程序，用于对活人的背外侧前额叶皮层 (DLPFC) 进行采样。我们将分析 500 多名活体和死后人类受试者的基因组、转录组（整体和单细胞）、蛋白质组、代谢组和脂质组。对这些数据的分析将识别区分生前和死后状态的分子特征。我们将利用这些见解来确定它们在多大程度上混淆了阿尔茨海默病和相关痴呆症的尸检研究。最后，我们将把这些多组学数据集与同一个体的神经影像和神经认知评估相整合。据我们所知，拟议的实验和分析将包括（1）对活体人类大脑进行最大的分子研究，（2）对活体和死后人类脑组织进行最大的分子比较，以及（3）将大脑的多组分子谱与同一活体个体的神经影像和深层神经认知表型配对的最大努力。我们预计，通过向科学界免费提供这一丰富的数据集，人类大脑生物学以及阿尔茨海默病和相关痴呆症发病机制的知识将取得根本性进展。