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 中枢神经系统的发育需要多个调节系统之间精心策划的相互作用 决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 控制我们最基本行为和复杂认知过程的复杂神经网络。作为一个 DNA序列和基因表达之间的中间调控域，表观遗传机制可以 对大脑发育产生巨大影响，其规模我们才刚刚开始认识到。一 近年来表观遗传学领域的重大进展是基因组新修饰的发现 DNA，例如 5-羟甲基胞嘧啶 (5hmC)，以及安装、移除和解释这些DNA的分子途径 修饰，在神经系统中高度丰富，并受到神经元的动态调节 生理和病理条件下的活性。 P01 的总体目标是 系统性方法来了解表观基因组和转录组的全局和特定变化 利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的一种构成现象，是一种良好的神经发生机制。 建立了由定义的阶段组成的神经发育模型，这些阶段起源于神经干 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。这种现象也代表了惊人的结构可塑性，并且已被 研究表明，它有助于关键的大脑功能，而其失调则与多种疾病有关 神经系统和退行性疾病。海马神经发生过程的表征可能 最终为基于细胞移植的治疗策略提供修复中枢神经系统的信息 中风、损伤或神经系统疾病。 将啮齿类动物成年海马神经发生的结果与人类诱导多能干细胞相结合 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、人类 iPSC、化学生物学、高通量 测序、生物信息学、电生理学和移植。研究顺利完成 项目将指导未来对 DNA 修饰失调在神经发育中的作用的研究 疾病并促进新技术方法的开发来识别表观遗传标记 高分辨率。