Mechanisms regulating neural stem cell maintenance in the dentate gyrus

项目摘要 邦德博士的主要职业目标是经营她自己的独立学术研究小组，广泛研究 大脑发育原理如何被用来理解和操纵成人大脑的可塑性和 再生。为了实现这一目标，邦德博士必须接受单细胞生物学技术方面的培训并取得进展 她的事业发展。拟议的研究和职业发展计划是专门设计的 以完成邦德博士未完成的训练，并为她职业生涯的下一个独立阶段做好准备。该计划包括 新技术技能的研究培训，包括体外延时成像、单细胞RNA测序和 大规模组学数据集的生物信息学分析，以及职业发展培训，包括赠款 写作、实验室管理、指导和科学交流技能。拟议的研究将是 在宾夕法尼亚大学佩雷尔曼医学院的直接指导下进行。 宋洪军，神经科学系教授，世界著名神经干细胞专家 生物学。佩雷尔曼医学院拥有为学员提供的特殊资源，包括扩展的核心 设施，最先进的实验室空间，以及重要的职业发展培训和资源，这将 共同为执行拟议的研究和职业发展计划提供理想的环境。 拟议的研究的主要目的是了解发育过程和分子 促进齿状回神经干细胞静止和发育后维持的机制。一个 将采用多管齐下的方法，包括单细胞、候选基因和转录组范围的方法。 首先，目标1中的克隆谱系追踪和延时成像实验将确定时间和细胞 预测神经干细胞在新生儿发育期间转变为静止状态的行为。然后，基因 AIM 2中的缺失实验将调查β1-整合素信号是如何正确建立 在新生儿发育期间静止的神经干细胞库，随后可能会有长期的 对成人神经发生的影响。最后，在目标3中，新生儿神经干细胞的单细胞RNA测序 发展将揭示驱动神经干细胞静止和维持的分子级联 新生儿齿状回发育。这项拟议的研究与国家心理研究所很好地结合在一起 健康对基础研究的兴趣旨在了解复杂的生物过程 神经发育。拟议项目的结果将促进我们对神经干细胞的理解 维护，并将长期应用于增强神经可塑性和神经再生。

Project Summary Dr. Bond’s primary career goal is to run her own independent academic research group broadly investigating how principles of brain development can be used to understand and manipulate adult brain plasticity and regeneration. To accomplish this goal, Dr. Bond must gain training in single-cell biology techniques and advance her career development. The proposed research and career development plan has been specifically designed to fulfill Dr. Bond’s unmet training and prepare her for the next independent stage of her career. The plan includes research training in new technical skills, including ex-vivo time-lapse imaging, single-cell RNA-sequencing, and bioinformatic analysis of large-scale omics datasets, as well as career development training, including grant writing, lab management, mentoring, and scientific communication skills. The proposed research will be conducted at the University of Pennsylvania’s Perelman School of Medicine under the direct mentorship of Dr. Hongjun Song, a professor in the Department of Neuroscience and a world-renowned expert in neural stem cell biology. The Perelman School of Medicine boasts exceptional resources for trainees, including expansive core facilities, state-of-the-art laboratory space, and significant career development training and resources, which will together serve as the ideal environment for carrying out the proposed research and career development plan. The main objective of the proposed research is to understand the developmental process and molecular mechanisms that promote dentate gyrus neural stem cell quiescence and maintenance beyond development. A multipronged approach, including single-cell, candidate gene, and transcriptome-wide methods, will be used. First, clonal lineage tracing and time-lapse imaging experiments in Aim 1 will determine the timing and cellular behaviors that predict neural stem cell transition into quiescence during neonatal development. Then, genetic deletion experiments in Aim 2 will investigate how β1-integrin signaling is required for proper establishment of the quiescent neural stem cell pool during neonatal development, which could subsequently have long-term effects on adult neurogenesis. Finally, in Aim 3, single-cell RNA-sequencing of neural stem cells across neonatal development will reveal the molecular cascade that drives neural stem cell quiescence and maintenance during neonatal dentate gyrus development. The proposed research is well-aligned with the National Institute of Mental Health’s interest in basic research aimed at understanding the complex biological processes that direct neurodevelopment. Results from the proposed project will advance our understanding of neural stem cell maintenance and will have long-term applications for enhancing neural plasticity and neuroregeneration.