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: 10522209
• 负责人: Ashley E Webb
• 金额: $ 35.06万
• 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: 2017-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10522209
• 关键词: Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Autophagocytosis; Biochemical Pathway; Biological Assay; Brain; Brain Diseases; CRISPR interference; Cell division; Cells; Chromatin; Cognition; Cognitive aging; Defect; Development; Disease; Epigenetic Process; FOXO3A gene; Failure; First Independent Research Support and Transition Awards; Functional disorder; Gene Expression; Genes; Genomic approach; Genomics; Goals; Health; Hippocampus (Brain); Homeostasis; Human; Image; Impaired cognition; Impairment; Lead; Learning; Light; Link; Longevity; Longitudinal Studies; Maintenance; Malignant Neoplasms; Memory; Metabolic; Mitochondria; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Outcome; Process; Publishing; Research; Rodent; Role; Sensory; Source; Spinal cord injury; Stroke; Testing; Time; Work; age related; aged; aging brain; base; behavioral phenotyping; cognitive performance; combat; epigenomics; genome-wide; healthy aging; improved; in vivo; live cell imaging; metabolomics; mood regulation; multiple omics; nerve stem cell; neurogenesis; normal aging; novel therapeutics; preservation; prevent; programs; screening; stem cell function; stem cell homeostasis; stem cells; therapeutic target; therapy development; tool; transcription factor; transcriptomics

PROJECT SUMMARY Cognitive decline is a major feature of aging and neurodegenerative diseases such as Alzheimer’s disease. Neurogenesis, the formation of new neurons, supports learning, memory, mood regulation, and sensory functions in the healthy mammalian brain. During aging, neurogenesis is dramatically reduced due to impairments in neural stem cell (NSC) pools. The mechanisms responsible for dysfunction of the NSC reservoir are not fully understood, but significant evidence implicates changes to the quiescent NSCs, which are the source of the neurogenic lineage. Ths work investigates the mechanisms responsible for failed activation of quiescent NSCs with age. This project is significant because identification of the mechanisms underlying dysfunction of quiescent NSCs with age will reveal strategies to restore new neuron formation in aging and neurodegeneration. Published and preliminary work shows that quiescent NSCs, though relatively dormant, are defective at the chromatin, gene expression, and metabolic levels with age. This study takes an integrated approach to reveal the specific target genes and processes responsible for defects in NSC quiescence with age. Specific Aim 1 will investigate how mitophagy regulates metabolic health of NSCs during aging. Aim 2 employs an integrated multi-omics strategy to fully elucidate the epigenomic and metabolic changes that occur the neurogenic lineage with age. Finally, Aim 3 will address the mechanisms by which NSCs return to quiescence, and the extent to which failure in this process results in depletion of the functional NSC pool with age. Collectively, this work will result in a comprehensive understanding of how dormant NSCs are affected by aging in the mammalian brain. In the long term, these studies have the potential to lead to the development of interventions to improve healthy aging and restore cognition in the context of neurodegeneration.

项目总结 认知功能减退是衰老和阿尔茨海默病等神经退行性疾病的主要特征。 神经发生，即新神经元的形成，支持学习、记忆、情绪调节和感觉 在健康的哺乳动物大脑中发挥作用。在衰老过程中，神经发生显著减少，原因是 神经干细胞池中的损伤。神经干细胞功能障碍的机制 水库尚未完全了解，但有重要证据表明，静止的NSCs发生了变化，这 是神经性血统的来源。这项工作调查了失败的机制 随着年龄的增长，静止的神经干细胞被激活。这个项目意义重大，因为确定了 静止期神经干细胞随年龄增长的潜在功能障碍将揭示恢复新神经元形成的策略 衰老和神经退化。已发表的和初步的工作表明，静止的神经干细胞，尽管相对 随着年龄的增长，在染色质、基因表达和代谢水平上都存在缺陷。这项研究采取了一项 揭示神经干细胞缺陷的特定靶基因和过程的综合方法 随着年龄的增长而平静下来。具体目标1将研究有丝分裂如何调节神经干细胞的代谢健康 衰老。AIM 2采用集成的多组学策略来充分阐明表观基因组和代谢 随着年龄的增长，神经性谱系发生的变化。最后，目标3将阐述通过哪些机制 NSC返回静止状态，以及此过程中的故障导致功能耗尽的程度 随年龄增长的NSC泳池。总体而言，这项工作将导致对休眠的NSC如何 会受到哺乳动物大脑老化的影响。从长远来看，这些研究有可能导致 制定干预措施，以改善健康老龄化和恢复认知 神经退行性变。