Epigenetic regulation of neurogenesis following perinatal hypoxic-ischemic brain injury

项目总结 围产期缺氧缺血性脑损伤(HI)是导致儿童神经系统疾病的主要原因之一 患有脑瘫、智力残疾和癫痫等后遗症的人群。尽管已知 由于未成熟大脑的可塑性，我们仍然很少有治疗方法来积极改善 这种疾病的潜在破坏性后果。神经发生是可塑性的一个方面， 在这种伤害后改善结果的潜力。神经干细胞和祖细胞(NSP)驻留在离散的 出生后大脑的不同区域，虽然我们知道它们可以改变行为，以回应众多 刺激，我们对这些刺激的基本机制仍然没有足够的了解 细胞对损伤做出反应。这份职业发展计划中描述的实验旨在使用 克隆分析中的先进策略，以更好地了解脑室下反应的异质性 带(SVZ)NSP到围产期HI。有了这些知识，我还建议为表观遗传学定义一个角色 活跃的DNA去甲基化是围产期缺氧缺血诱导神经发生的早期触发机制。最后我 目的研究Notch和BDNF基因甲基化模式的变化。 在NSP调节中的作用，将活跃的DNA去甲基化与已知的参与者联系在一起 神经发生。在这个过程中，我们还将使用新出现的单细胞RNA测序策略来 描述围产期HI后发生的转录组变化，并确定感兴趣的新途径 调节NSP对这种类型伤害的反应。与其他职业发展相结合 这项计划中描述的活动，这项计划将使我为进一步的独立研究生涯做好准备 探索围产期HI后的神经发生并将此知识转化为策略以更好地理解 并希望在脑损伤后的急性恢复期进行干预，以改善我们对 这样的病人。

PROJECT SUMMARY Perinatal hypoxic-ischemic brain injury (HI) is one of the leading causes of neurologic morbidity in the pediatric population with sequelae such as cerebral palsy, intellectual disability, and epilepsy. Despite the known plasticity of the immature brain, we still have very little in the way of therapies to actively ameliorate the potentially devastating consequences of this disease. Neurogenesis is one aspect of plasticity with the potential to improve outcomes after such injury. Neural stem and progenitor cells (NSPs) reside in discrete regions of the brain postnatally, and while we know that they can alter behavior in response to numerous stimuli, we still do not have a strong enough understanding of the fundamental mechanisms by which these cells respond to injury. The experiments described in this career development plan have been designed to use advanced strategies in clonal analysis to better understand the heterogeneity of the response of subventricular zone (SVZ) NSPs to perinatal HI. With this knowledge, I propose also to define a role for the epigenetic mechanism of active DNA demethylation as an early trigger for perinatal HI-induced neurogenesis. Finally I aim to investigate changes in the methylation patterns of Notch and BDNF, genes known to play important roles in NSP regulation, to link active DNA demethylation with known players in the phenomenon of neurogenesis. In the process we will also be using the emerging strategy of single cell RNA sequencing to describe transcriptome shifts that occur following perinatal HI and identify novel pathways of interest in regulating the response of NSPs to this type of injury. In conjunction with the other career development activities described in this proposal, this plan will prepare me for an independent research career further exploring neurogenesis after perinatal HI and translating this knowledge into strategies to better understand and hopefully intervene during the acute recovery period following brain injury to improve our management of such patients.