A multiscale investigation of the living human brain

对活人大脑的多尺度研究

• 批准号: 10668271
• 负责人: ALEXANDER W CHARNEY
• 金额: $ 66.26万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10668271
• 关键词: Address; Age; Alzheimer' s disease related dementia; Autopsy; Bilateral; Biology; Biopsy; Brain; Cells; Cessation of life; Cohort Analysis; Communities; Data; Data Analyses; Data Set; Deep Brain Stimulation; Dimensions; 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; Persons; 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; multimodal neuroimaging; multiple omics; neuroimaging; neuropathology; neuropsychiatry; single-cell RNA sequencing; trait; transcriptome; transcriptome sequencing; transcriptomics; virtual

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 由于无法访问活人的大脑，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，死亡和先前的情况的分子影响。人类大脑的痛苦过程是未知的，这种不确定性笼罩在该领域，成为几乎所有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。因此，分子生物学如何影响阿尔茨海默病和相关痴呆症的大脑结构和功能失调的整体叙述未能通过分子分析的能力来解决。在这里，我们通过活体大脑项目解决了这些严重的局限性，但我们对活体和死后的人类大脑组织进行了全面的多组学分子分析，LBP 的主要创新是一种安全、可扩展的采样程序。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，分析这些数据将识别区分活体的分子特征。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死后研究。据我们所知，所提出的实验和分析将包括（1）对活体人类大脑的最大分子研究，（2）对活体和死后人类大脑组织的最大分子比较。 ，（3）将大脑的多组学分子谱与来自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，我们预计人类大脑生物学和阿尔茨海默病及相关疾病发病机制的知识将取得根本性进展。痴呆症将通过向科学界免费提供这一丰富的数据集来实现。

项目成果

A study of gene expression in the living human brain.

对活人大脑中基因表达的研究。

• 发表时间: 2023-08-01
• 作者: Liharska, Lora E;Park, You Jeong;Ziafat, Kimia;Wilkins, Lillian;Silk, Hannah;Linares, Lisa M;Vornholt, Eric;Sullivan, Brendan;Cohen, Vanessa;Kota, Prashant;Feng, Claudia;Cheng, Esther;Moya, Emily;Thompson, Ryan C;Johnson, Jessica S;Rieder
• 通讯作者: Rieder

Comparison of gene expression in living and postmortem human brain.

活体和死后人类大脑中基因表达的比较。

• 发表时间: 2023-11-09
• 作者: Collado;Klei, Lambertus;Liu, Chunyu;Kleinman, Joel E;Hyde, Thomas M;Geschwind, Daniel H;Gandal, Michael J;Devlin, Bernie;Weinberger, Daniel R
• 通讯作者: Weinberger, Daniel R