Molecular mechanisms underlying the preservation of neural stem cell quiescence during aging

衰老过程中保持神经干细胞静止的分子机制

• 批准号: 9905339
• 负责人: Ashley E Webb
• 金额: $ 33.31万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905339
• 关键词: ASCL1 gene; Ablation; Adult; Age; Aging; Alzheimer' s Disease; Animals; Binding; Biological Assay; Bone Morphogenetic Proteins; Brain; Brain Diseases; Cell Count; Cell Cycle Regulation; Cell physiology; Cells; Cognitive; Critical Pathways; Cues; Data; Dementia; Deterioration; Development; Disease; Elderly; Environment; Equilibrium; FOXO3A gene; Future; Gene Combinations; Genes; Genetic Transcription; Goals; Impaired cognition; Impairment; Individual; Injury; Intervention; Knock-out; Knockout Mice; Learning; Longevity; Mediating; Memory; Methods; Modeling; Molecular; Mus; Natural regeneration; Neurodegenerative Disorders; Neurons; Outcome; Oxidative Stress; Pathway interactions; Physiological; Process; Protein Isoforms; Publishing; Research; Role; Sensory; Signaling Protein; Source; Spinal cord injury; Stroke; System; Testing; Time; Tissues; Work; age related; aged; aging brain; cognitive capacity; cognitive function; cost; exhaustion; experimental study; genome-wide; genome-wide analysis; improved; in vitro Assay; in vivo; injury and repair; innovation; insight; loss of function; mouse genetics; nerve stem cell; neurogenesis; novel therapeutics; overexpression; preservation; prevent; proteostasis; regenerative; regenerative therapy; relating to nervous system; repaired; response; response to injury; stem cell homeostasis; stem cell niche; stem cells; transcription factor

PROJECT SUMMARY/ABSTRACT 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 conserved “pro-longevity” transcription factor, FOXO3, preserves NSC quiescence 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 specific pathways regulated by FOXO3 in NSCs that preserve the quiescent state; 2) Investigate how FOXO3 and ASCL1 govern the balance between stem cell preservation and neurogenesis, a process that is drastically altered with age; and 3) Determine the extrinsic inputs that control FOXO3 activity and function. 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 reveal the dynamic and antagonistic interaction between FOXO3 and ASCL1, and test the extent to which levels or activity of these factors are responsible for reduced activation of NSCs with age. The third aim will be accomplished using a combination of mouse genetics and molecular methods to test the hypothesis that BMP signaling directly regulates FOXO3 expression in vivo to promote NSC quiescence during aging. 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 to counter the loss of NSC function during aging. This work is significant because it will determine why NSC activation is reduced in the aged brain, and uncover strategies to reverse it. This proposed research is innovative because it will use a unique system to elucidate the direct, genome-wide mechanisms that promote adult NSC quiescence, and parlay these findings into the in vivo setting. 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.

项目概要/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目前尚不清楚。 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 长期目标是确定导致 NSC 功能丧失的机制。 随着年龄的增长，并发现利用这些细胞的再生能力来增加的干预措施 该提案的目的是确定老年人和患病个体的功能。 保守的“长寿”转录因子 FOXO3 在衰老过程中保持 NSC 静止。 中心假设是 FOXO3 直接调节靶基因和通路网络，这些基因和通路对于 该假设将通过追求以下具体目标来检验： 1）确定NSCs中FOXO3调控的保持静止状态的具体通路； 2) 研究FOXO3和ASCL1如何控制干细胞保存和神经发生之间的平衡， 随着年龄的增长而发生显着改变的过程；以及 3) 确定控制 FOXO3 活性的外在输入 第一个目标将通过结合原代成年小鼠 NSC 模型来实现。 功能丧失和过度表达的静止方法来检验 FOXO3 直接 通过调节特定基因和途径促进静止。 方法揭示 FOXO3 和 ASCL1 之间的动态和拮抗相互作用，并测试其程度 这些因子的水平或活性会随着年龄的增长而减少 NSC 的激活。 将使用小鼠遗传学和分子方法的结合来完成，以检验以下假设： BMP 信号传导直接调节体内 FOXO3 的表达，以促进衰老过程中 NSC 的静止。 该项目的成果将是确定 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，并揭示了对抗 NSC 功能丧失的策略 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，以及 这项拟议的研究具有创新性，因为它将使用独特的系统来逆转它。 阐明促进成人 NSC 静止的直接全基因组机制，并利用这些发现 这项工作将为基因网络如何协调提供关键的机制见解。 年轻和衰老的神经干细胞中，有可能揭示认知衰退的新机制 老化期间。