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: 9308228
• 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/9308228
• 关键词: ASCL1 gene; Ablation; Adult; Age; Aging; Alzheimer' s Disease; Animals; Binding; Biological Assay; Biological Preservation; 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; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; 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; Stem cells; 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; nerve stem cell; neurogenesis; novel therapeutics; overexpression; prevent; proteostasis; regenerative; regenerative therapy; relating to nervous system; repaired; response; response to injury; 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.

项目总结/摘要 在衰老过程中，大脑中神经干细胞（NSC）形成新神经元的能力降低，但神经干细胞（NSC）在衰老过程中的作用可能会减弱。 神经干细胞功能恶化的分子机制尚不清楚。目前有一个关键的 需要了解神经干细胞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。长期目标是确定造成NSC功能丧失的机制 并发现利用这些细胞的再生能力来增加认知能力的干预措施 在老年和患病个体中发挥作用。本建议的目的是确定机制， 保守的“促长寿”转录因子FOXO 3在衰老过程中保持NSC的静止。的 核心假设是FOXO 3直接调节靶基因和途径的网络，这些基因和途径对于 在老化过程中保存NSC。将通过追求以下具体目标来检验这一假设： 1)确定FOXO 3在保持静止状态的NSC中调节的特定途径; 2)研究FOXO 3和ASCL 1如何控制干细胞保存和神经发生之间的平衡， 这一过程随着年龄的增长而急剧改变; 3）确定控制FOXO 3活性的外在输入 和功能第一个目标将通过结合原代成年小鼠NSC模型来实现 静止期功能丧失和过表达的方法来检验FOXO 3直接 通过调节特定的基因和途径促进静止。第二个目标将使用 方法揭示FOXO 3和ASCL 1之间的动态和拮抗相互作用，并测试FOXO 3和ASCL 1之间的相互作用程度。 这些因子的哪些水平或活性是导致NSC随年龄增长而活化减少的原因。第三个目标 将使用小鼠遗传学和分子方法的组合来完成，以测试假设， BMP信号直接调节体内FOXO 3表达，以促进衰老过程中NSC的静止。的 该项目的结果将是确定FOXO 3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。 衰老这项工作是重要的，因为它将确定为什么NSC激活在老年大脑中减少， 发现扭转它的策略。这项拟议的研究是创新的，因为它将使用一个独特的系统， 阐明促进成体NSC静止的直接的全基因组机制，并利用这些发现 进入体内环境。这项工作将为基因网络如何协调提供关键的机制见解 在年轻和衰老的神经干细胞中，并有可能揭示认知能力下降的新机制。 在老化过程中。