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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. .

项目总结/文摘