Transcriptional regulation of post-embryonic neuronal maturation

胚胎后神经元成熟的转录调控

• 批准号: 10621506
• 负责人: Haosheng Sun
• 金额: $ 8.43万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621506
• 关键词: Acute; Adult; Affect; Atlases; Award; Behavioral; Bioinformatics; Brain; Caenorhabditis elegans; Cell Lineage; Cell Nucleus; Chromatin; Chronic; Complex; Data; Data Set; Development; Disease; Disease susceptibility; Embryo; Embryonic Development; Environment; Environmental Risk Factor; Etiology; Event; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Risk; Genetic Screening; Genetic Transcription; Genomics; Goals; Human; Impairment; Intellectual functioning disability; Lead; Life; Methods; MicroRNAs; Mitotic; Molecular; Morphology; Nematoda; Nervous system structure; Neurodevelopmental Disorder; Neurons; Neurosciences Research; Organism; Parents; Pathway interactions; Phase; Physiology; Post-Transcriptional Regulation; Postdoctoral Fellow; Process; Regulation; Regulator Genes; Regulatory Element; Reporter; Reporter Genes; Research; Research Proposals; Role; Sensory; Specific qualifier value; Specificity; Stereotyping; Stimulus; Sum; Synapses; System; Testing; Transcriptional Regulation; Vertebrates; Work; autism spectrum disorder; axon guidance; behavioral plasticity; bioinformatics tool; brain tissue; cell type; experimental study; improved; insight; migration; mutant; nervous system development; neurodevelopment; neurotechnology; new therapeutic target; novel; perinatal period; post-doctoral training; postnatal development; postnatal period; predictive test; programs; relating to nervous system; synaptogenesis; tool; transcription factor; transcriptome; transcriptomics; young adult

PROJECT SUMMARY During the complex and intricately-timed sequence of nervous system development and maturation, significant and persistent disruptions to the dynamic regulatory process through genetic and environmental risks can result in neurodevelopmental disorders. Neuroscience research has contributed much to our understanding of early neural development in the embryonic and perinatal periods including neuronal specification, neuronal migration, axonal guidance/outgrowth, and synaptogenesis. The period from early post-natal life to young adulthood is equally critical for proper development of the mature brain, as extensive structural and behavioral plasticity are observed during these periods. However, much less is known about the molecular regulatory mechanisms underlying neuronal maturation during post-natal development. In my post-doctoral work/K99 phase of the award, I developed and optimized a method to isolate single neuron types for genomics profiling. Using this method, in combination with the genetic amenability of the C. elegans system, I profiled the transcriptome and chromatin accessibility of the nervous system throughout early post-natal development to young adulthood and identified a conserved pathway, initiated by the microRNA lin-4 (mir-125 in vertebrates), that controlled many but not all developmental-regulated, neuron-specific gene expression changes that underlie neuronal maturation. In Aim 1, using the genomic profiling data as an entry point, I will take a 2- pronged approach to identify additional, novel regulators of neuronal maturation. First, I will implement bioinformatics tools to extract common cis-regulatory motifs from developmentally regulated genes and predict/test candidate transcriptional regulators. Second, using validated developmentally-regulated gene reporters from my profiling, I will conduct unbiased forward genetic screens to identify novel regulators of neuronal maturation. In Aim 2, I will use advanced neurotechnology tools to examine the role of environmental stimuli (sensory-induced neuron activity) on neuronal maturation. First, I will examine how acute and chronic inhibition of activity in target neurons, during different developmental windows, affects single neuron developmental transcriptomes and chromatin accessibility. In addition, the interaction between pathways regulating neuronal maturation through environmentally-induced activity versus intrinsic genetic mechanisms will be examined using approaches as in Aim 1. The proposed research will increase our understanding of the genetic and environmental regulatory mechanisms underlying normal post-natal neurodevelopment, improve our understanding of the etiology of neurodevelopmental disorders, and reveal novel therapeutic targets. The successful completion of this project will provide a platform for future experiments aimed at understanding gene-environment interplay in the transcriptional regulation of nervous system development and function.

项目摘要 在神经系统发育和成熟的复杂和错综复杂的时间序列中， 通过遗传和环境风险对动态调节过程的持续破坏， 导致神经发育障碍。神经科学研究对我们理解 胚胎期和围产期的早期神经发育，包括神经元特化、神经元分化、神经元分化和神经元分化。 迁移、轴突引导/生长和突触发生。从出生后早期到年轻的时期 成年对于成熟大脑的适当发育同样重要，因为广泛的结构和行为 在这些期间观察到可塑性。然而，对分子调控机制的了解却少得多。 出生后发育过程中神经元成熟的潜在机制。在我的博士后工作中/K99 在获奖的第一个阶段，我开发并优化了一种方法来分离单个神经元类型用于基因组学分析。 利用该方法，结合C. elegans系统，我分析了 转录组和染色质可及性的神经系统在整个早期出生后的发展， 并确定了一个保守的途径，由microRNA lin-4（脊椎动物中的mir-125）启动， 控制了许多但不是所有发育调节的神经元特异性基因表达变化， 是神经元成熟的基础在目标1中，使用基因组分析数据作为切入点，我将采用2- 一个突出的方法来确定额外的，新的调节神经元成熟。首先，我将实施 生物信息学工具，从发育调控基因中提取共同的顺式调控基序， 预测/测试候选转录调节子。第二，使用经过验证的发育调控基因 从我的分析报告，我将进行公正的遗传筛选，以确定新的监管机构， 神经元成熟在目标2中，我将使用先进的神经技术工具来研究环境因素的作用。 刺激（感觉诱导的神经元活动）对神经元成熟的影响。首先，我将研究急性和慢性 在不同发育窗期间，靶神经元中活性抑制影响单个神经元 发育转录组和染色质可及性。此外，途径之间的相互作用 通过环境诱导活性与内在遗传机制调节神经元成熟 将使用目标1中的方法进行审查。拟议的研究将增加我们对 遗传和环境调节机制的基础正常出生后神经发育，改善 我们的神经发育障碍的病因学的理解，并揭示新的治疗目标。的 该项目的成功完成将为今后旨在了解 基因-环境相互作用在神经系统发育和功能的转录调节中。