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 在神经系统发展和成熟的复杂且错综复杂的序列中，显着 并通过遗传和环境风险持续造成动态调节过程 导致神经发育障碍。神经科学研究为我们的理解做出了很大的贡献 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/产物和突触发生。从产后早期生活到年轻的时期 成年对于广泛的结构和行为，对成熟大脑的正常发展同样至关重要 在这些时期内观察到可塑性。但是，关于分子调节的知之甚少 产后发育过程中神经元成熟的基础机制。在我的博士后工作/K99 奖项的阶段，我开发了一种分离单个神经元类型的方法进行基因组学分析。 使用这种方法，结合了秀丽隐杆线虫系统的遗传性舒适性，我介绍了 整个产后早期发育中神经系统的转录组和染色质的可及性 成年并确定了由MicroRNA LIN-4（脊椎动物中的miR-125）发起的保守途径， 这控制了许多但并非全部受发育调节的，神经元特异性的基因表达改变， 神经元成熟基础。在AIM 1中，使用基因组分析数据作为入口点，我将使用2- 识别神经元成熟的其他新型调节剂的李子方法。首先，我将实施 生物信息学工具从发育受调节的基因中提取常见的顺式调节基序 预测/测试候选转录调节器。其次，使用经过验证的发育中调节的基因 我的分析记者，我将进行公正的前向遗传筛选，以识别新颖的调节因子 神经元成熟。在AIM 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性）对神经元成熟。首先，我将研究急性和慢性 在不同的发育窗口中，抑制目标神经元中的活性会影响单个神经元 发育转录组和染色质可及性。另外，途径之间的相互作用 通过环境诱导的活性与内在遗传机制来调节神经元成熟 将使用AIM 1中的方法进行检查。拟议的研究将增加我们对 遗传和环境调节机制正常产后神经发育，改善 我们对神经发育障碍的病因的理解，并揭示了新的治疗靶点。这 该项目的成功完成将为以后的实验提供一个平台，以理解 神经系统发育和功能的转录调控中的基因环境相互作用。