Investigation of impaired neural stem cell activation in Alzheimer's Disease

阿尔茨海默氏病神经干细胞活化受损的研究

基本信息

批准号：
10624857
负责人：
Ashley E Webb
金额：
$ 40.41万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624857
关键词：
3xTg-AD mouse ATAC-seq Ablation Acceleration Address Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Area Atrophic Autopsy Brain Brain Injuries CRISPR screen CRISPR/Cas technology Cell Cycle Cell Differentiation process Cell Nucleus Cell division Cells Chromatin Communities Cytoplasmic Granules Data Disease Epigenetic Process Future Gene Expression Genes Genetic Transcription Genomic approach Goals Hippocampus Human Human Pathology Image Impaired cognition Impairment Individual Intervention Investigation Knowledge Late Onset Alzheimer Disease Learning Link Memory Memory Loss Metabolic Methods Mitochondria Nerve Degeneration Neurodegenerative Disorders Neurons Pathway interactions Population Process Resolution Risk Factors Rodent Sampling Source Time Work aging brain candidate identification cognitive performance dentate gyrus entorhinal cortex epigenomic profiling epigenomics excitatory neuron experience functional disability functional genomics gene network healthy aging human tissue improved interest metabolomics mood regulation mouse model multiple omics nerve stem cell neurogenesis prevent ratiometric self-renewal single nucleus RNA-sequencing stem cell function stem cell population therapy development transcriptomic profiling transcriptomics

项目摘要

PROJECT SUMMARY Alzheimer’s Disease (AD) is a devastating neurodegenerative disease that causes severe atrophy in the hippocampal area. The dentate gyrus of the mammalian hippocampus harbors populations of quiescent neural stem cells (NSCs) that can re-enter the cell cycle and differentiate into functional excitatory neurons. This process of neurogenesis supports learning and memory functions, as well as healthy mood regulation. However, in aging and AD, levels of neurogenesis sharply decline, and work in rodents has demonstrated a functional link between levels of neurogenesis and cognitive performance. Although quiescent NSCs are the source of new neurons, the current understanding of how these cells are impacted in AD is extremely limited. Preliminary work shows that quiescent NSCs are defective in a mouse model of AD. Moreover, these cells are particularly vulnerable to damage during aging, which is the greatest risk factor for AD. This proposal takes an integrated, multiomics approach to address the critical question of how the quiescent pool is affected in AD. Using a well-established mouse model and human tissue, specific Aim 1 will define the transcriptomic and epigenomic changes at the single cell level in AD. Work in Aim 2 will employ metabolomics to fully elucidate the metabolic changes that occur in AD. Lastly, Aim 3 will use a functional transcriptomics screen targeting central pathways in quiescent NSCs to identify how these cells are selectively vulnerable in AD. Together this work will result in a comprehensive understanding of how dormant NSCs are affected in a mouse model of AD as well as in human tissue. This study will provide key data to the neurodegeneration community that can be leveraged for functional studies and the development of interventions to prevent, treat and even cure neurodegeneration in the long term.

项目概要阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，会导致大脑严重萎缩海马区。哺乳动物海马的齿状回拥有静止的神经群体。干细胞（NSC）可以重新进入细胞周期并分化为功能性兴奋性神经元。神经发生过程支持学习和记忆功能以及健康的情绪调节。然而，在衰老和 AD 中，神经发生水平急剧下降，在啮齿类动物中的研究表明，尽管静止的神经干细胞是神经发生水平和认知表现之间的功能联系。作为新神经元的来源，目前对这些细胞在 AD 中如何受到影响的了解极其有限。初步研究表明，AD 小鼠模型中的静止 NSC 存在缺陷。特别是老化过程中的脆弱损伤，这是 AD 的最大风险因素。综合的多组学方法来解决 AD 中静态池如何受到影响的关键问题。使用完善的小鼠模型和人体组织，特定目标 1 将定义转录组和目标 2 中的工作将利用代谢组学来充分阐明 AD 中单细胞水平的表观基因组变化。最后，Aim 3 将使用针对 AD 的功能转录组学筛选。静态 NSC 中的中心通路，以确定这些细胞在 AD 中如何选择性脆弱。这项工作将全面了解 AD 小鼠模型中休眠的 NSC 如何受到影响这项研究将为神经退行性疾病界提供关键数据。用于功能研究和开发预防、治疗甚至治愈的干预措施长期来看，神经退行性变。