Development of novel genomic approaches for profiling cellular temporal-spatial dynamics of neurogenesis in Aging and Alzheimer's disease

开发新的基因组方法来分析衰老和阿尔茨海默病神经发生的细胞时空动力学

• 批准号: 10434335
• 负责人: Junyue Cao
• 金额: $ 85.69万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434335
• 关键词: Abnormal Cell; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Autopsy; Brain; Brain Diseases; Brain region; Cell Communication; Cell Differentiation process; Cell Proliferation; Cells; Data Set; Detection; Development; Disease; Event; Foundations; Frequencies; Functional disorder; Gene Expression; Gene Expression Regulation; Generations; Genetic; Genomic approach; Genomics; Goals; Heterogeneity; Hippocampus (Brain); Homeostasis; Human; Impairment; Libraries; Longevity; Maps; Messenger RNA; Methodology; Methods; Mission; Molecular; Molecular Profiling; Mus; Neurodegenerative Disorders; Neurons; Outcome; Pathologic; Play; Population; Preparation; Prevention strategy; Process; Protein Isoforms; Public Health; Regulation; Research; Resolution; Role; Sampling; System; Techniques; Tissues; United States National Institutes of Health; Work; adult neurogenesis; aged; aging brain; brain cell; cost; design; disability; effective therapy; in vivo; molecular dynamics; nerve stem cell; nervous system disorder; neurogenesis; neuropsychiatric disorder; neurotransmission; new therapeutic target; newborn neuron; novel; novel strategies; programs; rational design; relating to nervous system; stem; stem cell niche; therapeutic target; transcriptome; transcriptomics

PROJECT SUMMARY Adult neurogenesis is emerging as an important player in maintaining brain homeostasis and normal functions. The dysfunctions of neurogenesis have been associated with aging and neurological disorders, including Alzheimer’s disease (AD). The ability to systematically map the molecular dynamics of neurogenesis at single- cell resolution could serve as a foundation for a systematic effort to better understand the molecular events that give rise to abnormal cell states in aging and diseases. While the rapid advances in single-cell genomics are creating unprecedented opportunities to explore molecular heterogeneity in mammalian brains, nearly all such methods are restricted to low throughput and fail to recover the heterogeneity and dynamics of the profoundly rare cell states in adult neurogenesis (e.g., less than 0.1% of the cell population in the brain). Herein, we propose to develop novel methodologies that enable a comprehensive view of temporal-spatial dynamics of neurogenesis during aging and Alzheimer's disease (AD) in both human and mouse brains. Specifically, we will first develop a novel high-throughput, low-cost single-cell genomics approach, sciNext1000, to profile the molecular heterogeneity of four million cells from post-mortem human hippocampal samples. This approach will be powerful because we can not only quantitatively characterize the frequency of human adult hippocampal neurogenesis at single-cell resolution, but also identify the transcriptome features associated with impaired neurogenesis in aging and AD at isoform resolution. In addition, we will develop another novel single-cell genomic technique, sci-Div- seq, to enhance the detection of newborn neurons, and identify the cellular differentiation trajectories and associated transcriptomic features of adult neurogenesis in young and aged mouse brains. The resulting dataset will advance our understanding of gene regulation in neurogenesis across different neural lineages and constitute a significant step towards a comprehensive characterization of the molecular mechanism underlying neurogenesis impairment in aging. In addition to the internal molecular programs, the neurogenesis process is controlled by aspects of environmental signals from the neural stem niche. We will apply a high-throughput spatial transcriptomic strategy to identify the cellular interactions and local microenvironment involved in adult neurogenesis in both human and mouse brains. These multi-pronged approaches will open a new paradigm for understanding the global molecular programs and environmental regulation of adult neurogenesis, thereby informing potential therapeutic targets to restore cell population homeostasis in aging and brain disorders.

项目摘要 成人神经发生正在成为维持大脑稳态和正常功能的重要参与者。 神经发生功能障碍与衰老和神经系统疾病有关，包括 阿尔茨海默氏病（AD）。系统地绘制神经发生分子动力学的能力 细胞分辨率可以作为系统努力的基础，以更好地了解分子事件 在衰老和疾病中引起异常细胞状态。而单细胞基因组学的快速进步是 创造前所未有的机会来探索哺乳动物大脑中的分子异质性，几乎所有这些 方法仅限于低吞吐量，无法恢复深刻的异质性和动力学 成年神经发生中的罕见细胞态（例如，大脑中细胞群的不到0.1％）。在这里，我们建议 开发新的方法，使神经发生的临时空间动力学综合视图 在衰老和阿尔茨海默氏病（AD）期间，人类和小鼠大脑中的衰老。具体来说，我们将首先开发 新型的高通量，低成本的单细胞基因组学方法Scinext1000，以介绍分子 来自死后人类海马样品的四百万个细胞的异质性。这种方法将是强大的 因为我们不仅可以定量地表征人类成人海马神经发生的频率 单细胞分辨率，但也确定与衰老中神经发生受损相关的转录组特征 和同工型分辨率的AD。此外，我们将开发另一种新型的单细胞基因组技术，科幻 - Seq，增强新生神经元的检测，并确定细胞分化的轨迹和 成年神经发生的相关转录组在年轻小鼠大脑中的相关特征。结果数据集 将促进我们对不同神经元中神经发生中基因调节的理解， 构成了朝着底层分子机制的综合表征迈出的重要一步 衰老中的神经发生障碍。除了内部分子程序外，神经发生过程是 受神经茎生态裂环境信号的各个方面的控制。我们将应用高通量 空间转录策略以识别成人涉及的细胞相互作用和局部微环境 人和小鼠大脑中的神经发生。这些多管齐的方法将为 了解成人神经发生的全球分子程序和环境调节 告知潜在的治疗靶标，以恢复衰老和脑部疾病中细胞群体稳态。