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

项目总结 在人类的一生中，专门的神经干细胞会产生新的神经元 动物。成年海马区的神经发生水平随着年龄的增长而下降，并受到很大影响。 由阿尔茨海默病(AD)等神经退行性疾病引起。成年海马区神经发生是 与认知功能、情绪和压力反应有关，其增强被认为是一种 减轻阿尔茨海默病影响的潜在策略。准确的血统追踪有助于理解 衰老和阿尔茨海默病如何改变成年神经干细胞的分裂动态。然而，目前的工具用于 血统追踪成年神经干细胞的分裂，以及它们随后在神经元中的成熟 他们的范围有限。这导致了成人神经发生的相互矛盾的模型，阻碍了 了解成人神经发生的真正潜力作为减少神经再生影响的方法的进展 广告。我们的建议旨在通过使用一种新的DNA/RNA条形码方法来研究 成年神经干细胞在小鼠AD模型中的克隆性和谱系。这项研究计划将与单一的- 海马区干细胞及其后代的细胞内源性条形码和转录图谱。 这将揭示正常衰老和受AD影响的大脑中神经干细胞的生命周期。一种特殊的 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，从而潜在地定义了新生的海马神经元的特性 在AD的发展过程中。我们的发现以后可能被用来设计新的治疗策略 与阿尔茨海默病中发生的神经元丢失作斗争。

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.