Uncovering Central Regulators of Neural Stem Cell Aging and Rejuvenation

项目总结/摘要 随着阿尔茨海默病（AD）发病率的不断增加，针对传统疾病的药物 尽管迄今为止病因学尚未成功，但从不同的角度来处理这种毁灭性疾病至关重要。 因此，神经干细胞（NSC）已成为一种潜在的治疗方法。神经干细胞（NSC）在神经系统中起着关键的作用。 在学习，情绪和记忆中的作用，通过在齿状核中持续产生新生神经元 海马回这种神经发生的过程在老年早期和阿尔茨海默病中受损。 此外，NSC的数量与人类AD的结果和人类AD中神经发生的调节相关。 小鼠模型可有助于认知损害或改善。因此，仍然需要 了解为什么NSC变得功能失调，以及如何使它们恢复活力以用于治疗。解决这些 为了解决这些问题，我们对年轻和年老的NSC进行了单细胞RNA测序。我们发现了一个基因 老年NSC无法激活的网络。我们的实验室发现了一种化合物 基因网络，并在老年小鼠中进行了测试。这种化合物可以维持高水平的NSC活化， 增加NSC池大小、神经发生和认知。这些影响在NSC生物学中是不可预见的， 揭示了神经干细胞的新型再生能力，而不会引发耗尽或加深静止。我 初步数据表明，这种药物独特地靶向一种染色质重塑因子，该因子在这一过程中起核心作用。 识别基因网络。相关证据和现有文献进一步支持这一点。因此，我假设 通过慢病毒在年轻小鼠中敲低该因子将重现NSC衰老的表型效应（Aim 1)而该因子的过表达足以促进NSC再生（Aim 2）。这将提供 支持我们的化合物通过针对这一因素的工作，并将建立机械的理解， 为什么神经干细胞在年龄下降，以及如何针对他们在阿尔茨海默氏症的复兴。的广泛使用 免疫组织化学、手术技术和相关的计算培训将该项目确立为一个 理想的培训机会。该培训计划包括获取干细胞生物学的各种技能， 神经科学，生物信息学专业课程，演讲和写作技巧的磨练，以及 职业发展，这将帮助我实现我的目标，成为一个成功的独立科学家在大脑 衰老我的导师迈克尔·博纳圭迪博士有着出色的训练记录， 神经发生和NSC领域。Bonaguidi实验室位于快速发展的Broad干细胞研究所内 在南加州大学，这是一个高度协作和动态的环境，为我的科学发展。

Project Summary/Abstract As the incidence of Alzheimer’s disease (AD) continues to increase and drugs targeting traditional disease etiology have thus far failed, it is critical to approach this devastating disease from different perspectives. Neural stem cells (NSC) have thus emerged as a potential therapeutic. Neural stem cells (NSCs) play a critical role in learning, mood, and memory by continuing to generate newborn neurons throughout life in the dentate gyrus of the hippocampus. This process of neurogenesis is impaired early in age and in Alzheimer’s disease. In addition, NSC numbers are correlated with AD outcome in humans and modulation of neurogenesis in mouse models can contribute to cognitive impairment or improvement. Thus, there remains a need to understand why NSC become dysfunctional and how to rejuvenate them for therapeutic use. To address these questions, we performed single-cell RNA sequencing upon young and old NSCs. We uncovered a gene network that older NSCs are unable to activate. Our lab discovered a compound predicted to activate this gene network and tested it in old mice. This compound can sustain high levels of NSC activation while increasing NSC pool size, neurogenesis, and cognition. These effects are unforeseen in NSC biology and reveal a novel regenerative capacity of NSCs without triggering depletion nor deepened quiescence. My preliminary data suggest that this drug uniquely targets a chromatin remodeling factor that is central in this identified gene network. Correlative evidence and existing literature further support this. Thus, I hypothesize that knockdown of this factor in young mice via lentivirus will recapitulate phenotypic effects of NSC aging (Aim 1) whereas overexpression of this factor is sufficient to promote NSC rejuvenation (Aim 2). This would provide support our compound works through targeting this factor and would establish mechanistic understanding of why NSCs decline in age and how to target them for rejuvenation in Alzheimer’s. The extensive use of immunohistochemistry, surgical techniques and associated computational training establish this project as an ideal training opportunity. This training plan incorporates acquisition of diverse skills in stem cell biology and neuroscience, specialized coursework in bioinformatics, the honing of presentation and writing skills, and career development that will help me achieve my goal of becoming a successful independent scientist in brain aging. My mentor, Dr. Michael Bonaguidi, has an exceptional training record and has been instrumental in the neurogenesis and NSC field. The Bonaguidi lab is located within the rapidly growing Broad Stem Cell Institute at USC, which is a highly collaborative and dynamic environment for my scientific development.