Transcriptional regulation of post-embryonic neuronal maturation

胚胎后神经元成熟的转录调控

• 批准号: 10621618
• 负责人: Haosheng Sun
• 金额: $ 7.18万
• 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/10621618
• 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.

项目概要 在神经系统发育和成熟的复杂且错综复杂的时序过程中，显着 遗传和环境风险对动态监管过程的持续破坏可以 导致神经发育障碍。神经科学研究对我们的理解做出了很大贡献 胚胎和围产期的早期神经发育，包括神经元规范、神经元 迁移、轴突引导/生长和突触发生。从产后早期到青年时期 成年期对于成熟大脑的正常发育同样重要，因为广泛的结构和行为 在这些时期观察到可塑性。然而，人们对分子调控的了解却少之又少。 产后发育过程中神经元成熟的机制。在我的博士后工作/K99 在获奖阶段，我开发并优化了一种分离单个神经元类型以进行基因组分析的方法。 使用这种方法，结合秀丽隐杆线虫系统的遗传适应性，我分析了 神经系统转录组和染色质在产后早期发育过程中的可及性 并确定了由 microRNA lin-4（脊椎动物中的 mir-125）启动的保守途径， 控制许多但不是全部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- 多管齐下的方法来识别额外的、新颖的神经元成熟调节因子。首先，我将实施 从发育调控基因中提取常见顺式调控基序的生物信息学工具 预测/测试候选转录调节因子。其次，使用经过验证的发育调控基因 记者根据我的分析，我将进行公正的正向基因筛选，以确定新的监管者 神经元成熟。在目标 2 中，我将使用先进的神经技术工具来检查环境的作用 刺激（感觉诱导的神经元活动）对神经元成熟的影响。首先，我将检查急性和慢性 在不同的发育窗口期间抑制目标神经元的活动会影响单个神经元 发育转录组和染色质可及性。此外，途径之间的相互作用 通过环境诱导的活动与内在遗传机制调节神经元成熟 将使用目标 1 中的方法进行检查。拟议的研究将增加我们对 正常产后神经发育的遗传和环境调节机制，改善 我们对神经发育障碍病因的理解，并揭示新的治疗靶点。这 该项目的成功完成将为未来旨在理解的实验提供一个平台 基因-环境相互作用在神经系统发育和功能的转录调节中。