Epigenetic regulation of neurogenesis

神经发生的表观遗传调控

• 批准号: 9324035
• 负责人: HONGJUN SONG
• 金额: $ 105.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324035
• 关键词: Adult; Anatomy; Animal Model; Behavior; Bioinformatics; Biological Models; Biological Neural Networks; Biology; Brain; Brain Diseases; Brain region; Cell Count; Cell Proliferation; Cell Transplantation; Cell physiology; Cells; Chemicals; Complex; DNA; DNA Methylation; DNA Modification Process; DNA Repair; DNA Sequence; Data; Data Analyses; Data Set; Degenerative Disorder; Development; Dissection; Electrophysiology (science); Employee Strikes; Epigenetic Process; Future; Gene Expression; Genomic DNA; Genomics; Goals; High-Throughput Nucleotide Sequencing; Hippocampus (Brain); Human; In Vitro; Injury; Investigation; Learning; Mediating; Memory; Methodology; Methods; Modeling; Modification; Molecular; Molecular Target; Morphology; Mus; Nature; Nervous system structure; Neuraxis; Neurodevelopmental Disorder; Neurologic; Neurons; Neurophysiology - biologic function; Neurosciences; Outcome; Pathologic; Pathway interactions; Physiological; Population; Prevalence; Process; Property; Reader; Regulatory Element; Research Personnel; Research Project Grants; Resolution; Rodent; Role; Signal Pathway; Signal Transduction; Stem cells; Stroke; Synapses; System; Technical Expertise; Technology; Testing; Tetanus Helper Peptide; Therapeutic; Three-Dimensional Image; Time; Transplantation; base; cell behavior; cell type; cognitive process; data acquisition; demethylation; developmental neurobiology; epigenetic regulation; epigenome; genetic manipulation; in vivo; induced pluripotent stem cell; methylome; nerve stem cell; nervous system disorder; neural model; neurodevelopment; neurogenesis; neuron development; neuroregulation; new technology; next generation sequencing; novel; oxidation; programs; reconstruction; relating to nervous system; repaired; stem cell biology; structural biology; synaptogenesis; synergism; transcription factor; transcriptome; transcriptome sequencing

ABSTRACT Development of the central nervous system requires orchestrated interactions among several regulatory elements that determine the fate, properties, and functions of cells at any given time, ultimately leading to complex neural networks that control our most basic behaviors and complex cognitive processes. As an intermediate regulatory domain between DNA sequences and gene expression, epigenetic mechanisms can exert considerable influence on brain development on a scale that we are only beginning to appreciate. One major advance in the field of epigenetics in recent years is the discovery of novel modifications of genomic DNA, such as 5-hydroxymethylcytosine (5hmC), and molecular pathways to install, remove, and interpret these modifications, which are highly enriched in the nervous system and are dynamically regulated by neuronal activity under physiological and pathological conditions. The overarching goal of this P01 is to take a systematic approach to understand how global and specific changes in the epigenome and transcriptome regulate stem cell behavior, neuronal development and neuronal integration using hippocampal neurogenesis as a model system. Hippocampal neurogenesis is a constitutive phenomenon in the adult mammalian brain and is a well- established model for neural development that is comprised of defined stages, which originate with neural stem cell activation and result in the maturation and integration of a single neuronal subtype in an anatomically restricted region of the brain. This phenomenon also represents striking structural plasticity and has been shown to contribute to critical brain functions, whereas its dysregulation has been implicated in various neurological and degenerative disorders. Characterization of neurogenic processes in hippocampus may eventually inform cell transplantation-based therapeutic strategies to repair the central nervous system after stroke, injury or neurological disorders. Integrating results from adult hippocampal neurogenesis in rodents with human induced pluripotent stem cell (iPSC)-based models will allow for the identification of fundamental epigenetic principles governing neural development at the molecular, cellular, and systems levels. Our team includes experts in epigenetics, hippocampal neurogenesis, rodent stem cell biology, human iPSCs, chemical biology, high-throughput sequencing, bioinformatics, electrophysiology and transplantation. Successful completion of the research projects will guide future investigations into the role of dysregulated DNA modifications in neurodevelopmental disorders and facilitate the development of new technological approaches to identify epigenetic marks with high resolution.

抽象的 中枢神经系统的开发需要几种调节的互动 确定细胞在任何给定时间的命运，特性和功能的元素，最终导致 控制我们最基本的行为和复杂认知过程的复杂神经网络。作为 DNA序列与基因表达之间的中间调节结构域，表观遗传机制可以 在我们才开始欣赏的规模上对大脑发育产生相当大的影响。一 近年来，表观遗传学领域的主要进步是发现了基因组的新修饰 DNA，例如5-羟基甲基胞嘧啶（5HMC），以及用于安装，去除和解释这些的分子途径 修饰，高度富集在神经系统中，并由神经元动态调节 生理和病理条件下的活性。该P01的总体目标是采用 系统的方法来了解表观基因组和转录组的全球和特定变化 使用海马神经发生调节干细胞行为，神经元发育和神经元整合 作为模型系统。 海马神经发生是成年哺乳动物大脑中一种构成现象，是一种很好的 由定义阶段组成的神经发育的既定模型 细胞激活并导致单个神经元亚型在解剖学上的成熟和整合 大脑的限制区域。这种现象也代表着惊人的结构可塑性，并且已经 证明有助于关键的大脑功能，而其功能失调与各种相关 神经和退化性疾病。海马中神经源过程的表征可能 最终告知基于细胞移植的治疗策略，以修复中枢神经系统 中风，受伤或神经系统疾病。 在人类诱导多能茎的啮齿动物中，成年海马神经发生的结果整合 基于细胞（IPSC）的模型将允许识别控制神经的基本表观遗传原理 分子，细胞和系统水平的发展。我们的团队包括表观遗传学专家， 海马神经发生，啮齿动物干细胞生物学，人IPSC，化学生物学，高通量 测序，生物信息学，电生理学和移植。成功完成研究 项目将指导未来对DNA修饰失调在神经发育中的作用的调查 疾病并促进开发新技术方法，以识别具有的表观遗传标记 高分辨率。