Epigenetic regulation of neurogenesis following perinatal hypoxic-ischemic brain injury

围产期缺氧缺血性脑损伤后神经发生的表观遗传调控

• 批准号: 10133159
• 负责人: Ryan J Felling
• 金额: $ 19.98万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133159
• 关键词: Acute; BDNF gene; Base Excision Repairs; Behavior; Biological Markers; Biology; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain region; Brain-Derived Neurotrophic Factor; Cell Differentiation process; Cell physiology; Cells; Cerebral Palsy; Childhood; Cytosine; DNA; DNA Methylation; DNA Sequence; Data; Development Plans; Disease; Ensure; Environment; Epigenetic Process; Epilepsy; Family; Funding; GADD45A gene; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genetic Transcription; Growth Factor; Heritability; Heterogeneity; Human; Hypoxic-Ischemic Brain Injury; Impairment; Inflammatory; Injury; Intellectual functioning disability; Ischemia; Knock-out; Knowledge; Lead; Life; Link; Mediating; Mixed Function Oxygenases; Modification; Molecular; Morbidity - disease rate; Natural regeneration; Neurologic; Neurosciences; Organism; Paint; Pathway interactions; Patients; Perinatal; Perinatal Brain Injury; Perinatal Hypoxia; Phase; Phenotype; Play; Population; Process; Protein Family; Quality of life; Recovery; Regulation; Research; Rodent; Role; Societies; Stimulus; Techniques; Tetanus Helper Peptide; Therapeutic; Training; Transgenic Organisms; Translating; Translational Research; adult neurogenesis; brain repair; career; career development; cell regeneration; cell type; clinical application; cost; demethylation; design; epigenetic regulation; experimental study; gene induction; hypoxic ischemic injury; improved; improved outcome; in vivo; innovation; interest; ischemic injury; methylation pattern; methylomics; migration; nerve stem cell; neurogenesis; new therapeutic target; notch protein; novel; overexpression; postnatal; progenitor; repaired; response; single-cell RNA sequencing; sound; stem cell biology; stem cells; stroke recovery; subventricular zone; therapy design; transcriptome

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.

项目概要 围产期缺氧缺血性脑损伤（HI）是儿科神经系统疾病的主要原因之一 患有脑瘫、智力障碍、癫痫等后遗症的人群。尽管已知 尽管尚未成熟的大脑具有可塑性，但我们仍然缺乏积极改善大脑可塑性的治疗方法。 这种疾病可能造成毁灭性的后果。神经发生是可塑性的一方面 改善此类损伤后的结果的潜力。神经干细胞和祖细胞 (NSP) 存在于离散的细胞中 出生后的大脑区域，虽然我们知道它们可以根据许多情况改变行为 尽管我们对这些刺激的基本机制还没有足够深入的了解 细胞对损伤做出反应。本职业发展计划中描述的实验旨在使用 克隆分析的先进策略，以更好地了解室下反应的异质性 区 (SVZ) NSP 至围产期 HI。有了这些知识，我还建议定义表观遗传的作用 主动 DNA 去甲基化作为围产期 HI 诱导神经发生的早期触发机制。最后我 旨在研究 Notch 和 BDNF 甲基化模式的变化，这些基因已知发挥重要作用 NSP 调节中的作用，将活跃的 DNA 去甲基化与已知的现象中的参与者联系起来 神经发生。在此过程中，我们还将使用单细胞 RNA 测序的新兴策略来 描述围产期 HI 后发生的转录组变化并确定新的感兴趣途径 调节 NSP 对此类损伤的反应。与其他职业发展相结合 本提案中描述的活动，该计划将为我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，并将这些知识转化为更好地理解的策略 并希望在脑损伤后的急性恢复期进行干预，以改善我们的管理 这样的病人。

项目成果

Treatment and outcome of childhood cerebral sinovenous thrombosis.

儿童脑静脉血栓形成的治疗和结果。

• DOI: 10.1212/cpj.0000000000000720
• 发表时间: 2020
• 期刊: Neurology. Clinical practice
• 作者: Felling,RyanJ;Hassanein,SaharMA;Armstrong,Jennifer;Aversa,Luis;Billinghurst,Lori;Goldenberg,NeilA;Lee,JoEllen;Maxwell,EmilyC;Noetzel,MichaelJ;Lo,Warren
• 通讯作者: Lo,Warren