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.

摘要