Regulation of Neural Stem Cell Quiescence by FOXO3 During Aging

FOXO3 在衰老过程中调节神经干细胞静止

• 批准号: 10210272
• 负责人: Ashley E Webb
• 金额: $ 20.24万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210272
• 关键词: ASCL1 gene; Adult; Affect; Age; Aging; Alzheimer' s Disease; Behavior; Behavioral; Binding Sites; Brain; Brain Diseases; Cell Count; Cell Cycle; Cell physiology; Cells; ChIP-seq; Characteristics; Cognitive; Complex; Critical Pathways; DNA Damage; Data; Dementia; Deterioration; Disease; Equilibrium; FOXO3A gene; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Goals; Human; Impaired cognition; Individual; Intervention; Learning; Longevity; Maintenance; Mediating; Memory; Methods; Modeling; Molecular; Mus; Neurons; Outcome; Pathway interactions; Process; Regenerative capacity; Regulation; Research; Rodent; Sensory; Source; Testing; Therapeutic; Transgenic Mice; Work; age related; aged; aging brain; cell type; chromatin immunoprecipitation; cognitive function; cognitive performance; experimental study; improved; in vivo; innovation; insight; loss of function; nerve stem cell; neurogenesis; neuroregulation; overexpression; preservation; proteostasis; response; stem cell aging; stem cell function; stem cell homeostasis; stem cells; transcription factor

Abstract/Project Summary During aging, the ability of neural stem cells (NSCs) in the brain to form new neurons is reduced, but the molecular mechanisms underlying the deterioration of NSC function remain unclear. There is currently a critical need to understand the mechanisms by which NSCs are activated to form neurons, and why this process declines with age. The long term goal is to identify the mechanisms responsible for the loss of NSC function with age, and discover interventions that harness the regenerative capacity of these cells to increase cognitive function in aged and diseased individuals. The objective of this proposal is to identify the mechanisms by which the pro-longevity transcription factor FOXO3 maintains NSCs during aging. The central hypothesis is that FOXO3 directly regulates a network of target genes and pathways that are critical for preserving NSCs during aging. This hypothesis will be tested by pursuing the following specific aims: 1) Determine the mechanisms underlying FOXO3-mediated NSC quiescence. 2) Determine how changes in the FOXO3 network underlie the decline in NSC function with age. 3) Determine the extent to which FOXO3 can preserve stem cells in vivo during aging. The first aim will be accomplished by combining a model of primary adult mouse NSC quiescence with loss of function and overexpression approaches to test the hypothesis that FOXO3 directly promotes quiescence by regulating specific genes and pathways. The second aim will be performed using methods to test the extent to which levels, activity, or binding sites downstream of FOXO3 are responsible for observed gene expression changes in aging NSCs. The third aim will be accomplished using a transgenic mouse overexpressing FOXO3 under endogenous regulation to test the hypothesis that increasing levels of FOXO3 maintains NSCs in a quiescent state during aging, thereby increasing the pool of NSCs in old mice. The outcome of this project will be the identification of the mechanisms by which FOXO3 regulates NSC function, how these mechanisms deteriorate with age, and reveal a strategy that reverses the loss of NSCs in aging mice. This work is significant because it will determine why NSC activation is reduced in the aged brain, and reveal strategies to reverse it. This proposed research is innovative because it will be the first to elucidate a direct transcriptional mechanism to promote adult NSC quiescence. This work will provide key mechanistic insight into how gene networks are coordinated in young and aging NSCs, and have the potential to reveal new mechanisms underlying cognitive decline during aging.

摘要/项目摘要 在衰老过程中，大脑中的神经干细胞（NSC）形成新神经元的能力会降低，但 NSC 功能恶化的分子机制仍不清楚。目前存在一个关键的 需要了解 NSC 被激活形成神经元的机制，以及为什么这个过程 随着年龄的增长而下降。长期目标是确定导致 NSC 功能丧失的机制 年龄，并发现利用这些细胞的再生能力来提高认知能力的干预措施 在老年人和患病个体中发挥作用。该提案的目的是确定机制 长寿转录因子 FOXO3 在衰老过程中维持 NSCs。中心假设是 FOXO3 直接调节靶基因和通路网络，这对于衰老过程中保存 NSC 至关重要。 该假设将通过追求以下具体目标来检验：1）确定潜在的机制 FOXO3 介导的 NSC 静止。 2) 确定 FOXO3 网络的变化如何导致下降 NSC 功能随年龄增长。 3) 确定FOXO3在衰老过程中在体内保存干细胞的程度。 第一个目标将通过将原代成年小鼠 NSC 静止与丧失的模型相结合来实现 功能和过表达方法来检验 FOXO3 直接促进静止的假设 调节特定基因和途径。第二个目标将使用测试其程度的方法来实现 FOXO3 下游的哪些水平、活性或结合位点负责观察到的基因表达 老化 NSC 的变化。第三个目标将使用过度表达 FOXO3 的转基因小鼠来实现 在内源性调节下检验增加 FOXO3 水平可以维持 NSC 的假设 衰老过程中处于静止状态，从而增加了老年小鼠中 NSC 的数量。该项目的成果将 确定 FOXO3 调节 NSC 功能的机制，这些机制如何 随着年龄的增长而恶化，并揭示了一种逆转衰老小鼠中神经干细胞损失的策略。这项工作意义重大 因为它将确定衰老大脑中 NSC 激活减少的原因，并揭示逆转这种现象的策略。 这项拟议的研究具有创新性，因为它将是第一个阐明直接转录机制的研究 促进成体 NSC 静止。这项工作将为基因网络如何运作提供关键的机制见解 在年轻和衰老的神经干细胞中协调，并有可能揭示认知认知的新机制 衰老过程中下降。