Using Polylox DNA barcodes to lineage trace adult neural stem cells in Alzheimers Disease

项目摘要 新的神经元是在人类的整个生命周期中从专用的神经干细胞中产生的， 动物海马中的成年神经发生水平随着年龄的增长而下降， 神经退行性疾病，如阿尔茨海默病（AD）。成人海马神经发生是 与认知功能、情绪和应激反应有关，其增强被认为是 缓解AD影响的潜在策略。准确的血统追踪可以帮助理解 衰老和AD如何改变成体神经干细胞的分裂动力学。然而，目前的工具用于 谱系追踪成体神经干细胞的分裂，以及它们随后在神经元中的成熟， 局限于其范围。这导致了成人神经发生的相互冲突的模型，阻碍了 在理解成人神经发生作为减少神经发育不良影响的一种手段的真正潜力方面取得的进展 AD.我们的建议旨在通过使用新的DNA/RNA条形码方法来研究 小鼠AD模型中成体神经干细胞的克隆性和谱系。这项研究计划将匹配单一- 海马干细胞及其后代的细胞内源性条形码和转录谱。 这将揭示神经干细胞在正常衰老和受AD影响的大脑中的生命周期。特定 该项目的重点是选择性扩增或删除干细胞亚类的可能性 在AD进展过程中，从而可能定义新的海马神经元的特性， 在AD的发展过程中。我们的研究结果可以用来设计新的治疗策略， 对抗AD中神经元的丢失。

PROJECT SUMMARY New neurons are produced from dedicated neural stem cells throughout the lifespan of humans and animals. The level of adult neurogenesis in the hippocampus declines with age and is drastically affected by neurodegenerative disorders such as Alzheimer's disease (AD). Adult hippocampal neurogenesis is implicated in cognitive function, mood, and stress response and its augmentation is considered as a potential strategy for mitigating the effects of AD. Accurate lineage tracing could help in understanding how aging and AD alter the division dynamics of adult neural stem cells. However, current tools used to lineage trace the division of adult neural stem cells, and their subsequent maturation in neurons, are limited in their scope. This has contributed to conflicting models of adult neurogenesis, hindering progress in understanding the true potential of adult neurogenesis as a means of reducing the effects of AD. Our proposal aims to move the field forward by using a new DNA/RNA barcoding approach to study clonality and lineage of adult neural stem cells in a mouse AD model. This research plan will match single- cell endogenous barcoding and transcriptional profiling of the hippocampal stem cells and their progeny. This will uncover the life cycle of neural stem cells in the normal aging and AD-affected brain. A particular emphasis of the project is the possibility of selective expansion or deletion of subclasses of stem cells during AD progression, thereby potentially defining the properties of new hippocampal neurons born during the development of AD. Our findings could be later used to design new therapeutic strategies to combat the loss of neurons that occurs in AD.