Unraveling stem cell behaviors upon injury to the brain

候选人：我的首要目标是了解调控的分子机制 神经干细胞在动态平衡、再生和肿瘤中的自我更新和分化。至 为了实现这一目标，我正在追求干细胞生物学的职业生涯，专注于大脑。我的毕业工作主要集中在 关于患者脑肿瘤中不同分子干细胞群的特征和认识 它们在肿瘤发生中的作用。为了获得深入研究干细胞行为的经验 在体内调节后，我选择加入亚历山德拉·乔伊纳博士的实验室，研究发育神经生物学和 再生。在这里，我研究干细胞在发育中的和成人小脑修复过程中的功能。这个 这笔赠款的主要目的是提供我需要的技能和知识，以建立我自己的独立 研究计划。环境：乔伊纳博士的实验室为我提供了一个激励我进行研究的环境 和指导技能，开始了我作为独立调查员的职业生涯。在她的指导下，在 在同事的帮助下，加上支持性的制度环境，我会学到最精湛的 对体内干细胞研究至关重要的小鼠模型和发育生物学技术。除了……之外 Joyner博士、我的顾问和合作者将在基因组学/表观基因组学方法方面提供必要的培训 以补充我所需的知识和培训，以建立一个多学科的研究计划。 研究：大脑再生能力有限。我认为对基因调控网络的理解 调节神经干细胞/祖细胞群体的可塑性及其自我更新和分化的能力 对于发现如何刺激大脑的再生潜力至关重要。我们实验室最近发现 新生小脑具有令人惊讶的高再生潜力，因为它至少可以通过消融恢复 两种类型的神经元，使其成为发现成功所需的分子事件的优秀系统 再生。当颗粒细胞前体耗尽时，表达巢蛋白的祖细胞亚群 在Hedgehog(HH)依赖的神经元中，(NNP)改变其从胶质细胞到产生兴奋性颗粒神经元的命运 举止。此外，我发现在成人小脑中存在罕见的NEP样细胞，HH信号与损伤 协同扩大人口规模。然而，它们的再生产量是有限的。这项建议的目的是 识别控制非结缔组织再生反应的信号通路和基因调控网络 新生儿小脑的损伤，并确定它在成年人中有何不同。我将把老鼠的遗传学和 用全基因组转录/表观基因组分析来分析和比较基因的损伤模型 正常和损伤新生儿及成人小脑中单个核仁组成蛋白的表达谱。在体外和在 体内干细胞检测将确定刺激自我更新和重新编程的信号通路 再生，以及候选的促再生通路将被测试它们增强修复的能力。我的 这些发现将为在体内操纵干细胞以促进大脑修复提供基础。

Candidate: My overarching goal is to understand the molecular mechanism that regulate self-renewal and differentiation of neural stem cell during homeostasis, regeneration and in neoplasms. To achieve this goal, I am pursuing a career in stem cell biology, focusing on the brain. My graduate work focused on characterizing molecularly distinct stem cell populations in patient-derived brain tumors and understanding their roles in tumorigenesis. In order to gain in depth experience on studying how stem cell behaviors are regulated in vivo, I chose to join Dr. Alexandra Joyner’s laboratory to study developmental neurobiology and regeneration. Here, I study the function of stem cells during repair of the developing and adult cerebellum. The main purpose of this grant is to provide the skills and knowledge that I need to build my own independent research program. Environment: Dr. Joyner’s lab provides a stimulating environment for me to gain research and mentoring skills to launch my career as an independent investigator. Under her mentorship and with the help of my colleagues along with the supportive institutional environment, I will learn the most sophisticated mouse models and developmental biology techniques that are crucial to study stem cells in vivo. In addition to Dr. Joyner, my advisors and collaborators will provide necessary training in genomics/epigenomics approaches to supplement my required knowledge and training in order to establish a multidisciplinary research program. Research: Regeneration in the brain is limited. I submit that an understanding of the gene regulatory networks that regulate the plasticity of neural stem/progenitor populations and their ability to self-renew and differentiate is crucial for discovering how to stimulate the regenerative potential of the brain. Our lab recently discovered that the neonatal cerebellum has a surprisingly high regenerative potential as it can recover from ablation of at least two types of neurons, making it an excellent system to uncover molecular events required for successful regeneration. Upon depletion of granule cell precursors, a subpopulation of Nestin-expressing progenitors (NEPs) change their fate from glia to produce excitatory granule neurons in a Hedgehog (HH)-dependent manner. Furthermore, I found that rare NEP-like cells exist in the adult cerebellum, and HH signaling and injury synergize to expand the population. However, their regenerative yield is limited. The aim of this proposal is to identify the signaling pathways and gene regulatory networks that control the regenerative response of NEPs to injury in the newborn cerebellum and determine how it differs in the adult. I will combine mouse genetics and injury models with whole genome transcriptomic/epigenomic analyses to dissect and compare the gene expression profiles of individual NEPs in the normal and injured newborn and adult cerebellum. In vitro and in vivo stem cells assays will then identify signaling pathways that stimulate self-renewal and reprogramming during regeneration, and candidate pro-regenerative pathways will be tested for their ability to enhance repair. My findings will provide a basis for in vivo manipulation of stem cells to facilitate repair of the brain.