Transcriptional regulation of post-embryonic neuronal maturation

胚胎后神经元成熟的转录调控

基本信息

批准号：
10689088
负责人：
Haosheng Sun
金额：
$ 24.9万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
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/10689088
关键词：
ATAC-seq Acute Adolescent Adult Affect Afferent Neurons Award Behavioral Bioinformatics Brain Caenorhabditis elegans Cell Nucleus Chromatin Chronic Complex Data Data Set Development Disease Electrophysiology (science)Embryo Environment Environmental Risk Factor Etiology Event Future Gene Expression Regulation Genes Genetic Genetic Risk Genetic Screening Genetic Transcription Genomics Goals Human Impairment Individual Intellectual functioning disability Interneurons Knowledge Laboratories Lead Life Mentorship Methods MicroRNAs Molecular Morphology Nematoda Nervous System Neurodevelopmental Disorder Neurons Neurosciences Research Neurotransmitters Organism Pathway interactions Phase Phenotype Physiology Positioning Attribute Post-Transcriptional Regulation Postdoctoral Fellow Postembryonic Poverty Predisposition Preparation Primates Process Productivity Publishing Regulation Regulator Genes Reporter Genes Research Research Personnel Research Proposals Resolution Role Sensory Specific qualifier value Specificity Stereotyping Stimulus System Temperature Testing Training Transcriptional Regulation Universities Work autism spectrum disorder axon guidance behavioral plasticity bioinformatics tool brain tissue data integration design experience experimental study improved insight migration mutant nervous system development neural neurodevelopment neurotechnology new therapeutic target novel perinatal period post-doctoral training postmitotic postnatal postnatal development postnatal period postsynaptic presynaptic programs response skills synaptogenesis tool transcription factor transcriptome transcriptome sequencing transcriptomics young adult

项目摘要

PROJECT SUMMARY/ABSTRACT 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 the first part of my post-doctoral work, 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 will profile the transcriptome and chromatin accessibility of single neuron types throughout early post-natal development to young adulthood (Aim 1). In Aim 2, using the profiling data from Aim 1 as an entry point, I will take a 2-pronged approach to identify novel regulators of neuronal maturation. First, I will co-develop and implement bioinformatics tools to extract common cis-regulatory motifs from developmentally regulated genes and predict candidate transcriptional regulators. Second, using validated developmentally-regulated gene reporters in Aim 1, I will conduct unbiased forward genetic screens to identify novel regulators of neuronal maturation. In Aim 3, 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 2. 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 training phase of the award, conducted in the laboratory of Dr. Oliver Hobert and under the co- mentorship of Dr. Harmen Bussemaker and Dr. Stavros Lomvardas at Columbia University, outlines a comprehensive plan for the acquisition of technical and professional skills that will enable my transition to an independent research position. 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/摘要在神经系统发育和成熟的复杂且错综复杂的时间序列中，通过遗传和环境对动态监管过程造成重大和持续的破坏风险可能导致神经发育障碍。神经科学研究为我们做出了很大贡献了解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。这段时期从早期开始产后生活到成年早期对于成熟大脑的正常发育同样重要，因为广泛的在这些时期观察到结构和行为可塑性。然而，人们对它知之甚少产后发育过程中神经元成熟的分子调节机制。在第一个作为博士后工作的一部分，我开发并优化了一种分离基因组学单个神经元类型的方法分析。使用这种方法，结合秀丽隐杆线虫系统的遗传适应性，我将分析产后早期单个神经元类型的转录组和染色质可及性发展到青年期（目标 1）。在目标 2 中，使用目标 1 中的分析数据作为入口点，我将采取双管齐下的方法来识别神经元成熟的新调节因子。首先，我将共同开发和使用生物信息学工具从发育调控基因中提取常见的顺式调控基序并预测候选转录调节因子。其次，使用经过验证的发育调控基因目标 1 中的记者，我将进行公正的正向遗传筛选，以确定神经元的新型调节因子成熟。在目标 3 中，我将使用先进的神经技术工具来检查环境刺激的作用（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抑制如何在不同的发育窗口期间，目标神经元的活动影响单神经元的发育转录组和染色质可及性。此外，调节神经元通路之间的相互作用将检查通过环境诱导的活动与内在遗传机制的成熟使用目标 2 中的方法。拟议的研究将增加我们对遗传和正常产后神经发育的环境调节机制，改善我们的了解神经发育障碍的病因，并揭示新的治疗靶点。该奖项的培训阶段在 Oliver Hobert 博士的实验室和合作下进行在哥伦比亚大学 Harmen Bussemaker 博士和 Stavros Lomvardas 博士的指导下，概述了获得技术和专业技能的全面计划，使我能够过渡到独立研究职位。该项目的顺利完成将为未来的发展提供平台旨在了解神经转录调节中基因与环境相互作用的实验系统的开发和功能。。