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The Role of Fos and the BAF Complex in Neuronal Activity-Dependent Chromatin Remodeling and Gene Expression

Fos 和 BAF 复合物在神经元活动依赖性染色质重塑和基因表达中的作用

基本信息

批准号：
10572785
负责人：
Sara Trowbridge
金额：
$ 19.4万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10572785
关键词：
Advisory Committees Affect Animal Model Area Binding Binding Sites Brain CRISPR/Cas technology Cells Childhood Chromatin Chromatin Remodeling Factor Collection Complex Data Development Developmental Process Disease Disease model Distal Distal Enhancer Elements Enhancers Epilepsy Ethics Exhibits Fibroblasts Functional disorder Gene Expression Genes Genetic Genetic Databases Genetic Transcription Genetic Variation Genomics Heterozygote Human Human Activities Human Genetics Human Genome In Vitro Individual Intellectual functioning disability Knowledge Laboratories Life Light Mediating Mentors Mentorship Modeling Molecular Morbidity - disease rate Mus Neurodevelopmental Disorder Neuronal Plasticity Neurons Neurosciences Neurosciences Research Nucleic Acid Regulatory Sequences Pathogenesis Pathway interactions Patients Pediatric Neurology Phenotype Physicians Physiological Play Positioning Attribute Process Program Development Regulation Regulator Genes Regulatory Element Regulon Research Role Scientist Site Source Stimulus Techniques Technology Testing Therapeutic Time Training Variant Visual Cortex Work autism spectrum disorder behavioral phenotyping brain abnormalities career career development cell type childhood epilepsy chromatin remodeling dbSNP design developmental disease experimental study genetic variant human disease human embryonic stem cell human embryonic stem cell line human model in vitro Model in vivo in vivo Model insight mouse model neural circuit neurodevelopment neurogenetics new therapeutic target next generation sequencing novel therapeutics programs recruit response single-cell RNA sequencing synaptic pruning transcription factor translational neuroscience

项目摘要

Pediatric neurodevelopmental disorders (NDD), including pediatric epilepsy, autism spectrum disorder, and intellectual disability, represent a major source of morbidity, yet our therapeutic options remain limited. Development of novel therapies for NDD will require a deeper mechanistic understanding of normal and abnormal brain development. This proposal focuses on genetic programs that are activated in response to neuronal activity and that are fundamental to normal neurodevelopment and on-going neuronal plasticity throughout life. Fos is a major activity-dependent transcription factor that binds to distal enhancer elements and regulates downstream activity-dependent genetic programs in a cell-type-specific manner to promote key processes, including synaptic pruning and the recruitment of inhibition in the developing brain. Despite its role in key developmental processes, we do not understand how Fos is differentially targeted to cell-type-specific binding sites, nor how genetic variation at these sites impacts neurodevelopment and neuronal function. Interestingly, Fos has been shown to physically interact with the BAF chromatin remodeling complex, and it is possible that this interaction is critical to Fos function. Many BAF subunits, most frequently ARID1B, are implicated in human NDD, but whether the BAF complex regulates neuronal activity-dependent genetic programs, and how this underlies aspects of BAF complex-related NDD, is previously unexplored. The research in this proposal will address these gaps in knowledge by: (a) profiling Fos and BAF complex neuronal binding sites across the human genome; (b) assessing human genetic variants at these sites in individuals with NDD vs controls; and (c) determining the effects of BAF complex perturbation on neuronal activity-dependent genetic programs in vitro and in vivo. Overall, this work will lead to greater insight into how activity-dependent genetic programs contribute to NDD pathogenesis. Additionally, by identifying specific activity-regulated genes and pathways that are mis-regulated downstream of Fos and the BAF complex, these experiments could highlight novel therapeutic targets for NDD. This research is the basis for a five-year career development program designed to build on Dr. Trowbridge’s background in molecular neuroscience, pediatric neurology/epilepsy, and neurogenetics, by providing her with additional training in analysis of human sequencing data, use of in vitro and in vivo models of NDD, and next- generation sequencing technologies. Her primary mentor, Dr. Mike Greenberg, and her scientific advisory committee, Drs. Annapurna Poduri and Chris Walsh, will provide guidance in these areas, as well as mentorship in the rigorous and ethical conduct of translational neuroscience research. Thus the proposed training plan will position Dr. Trowbridge to launch her independent career as a clinician-scientist focused on understanding the role of activity-dependent genetic programs in NDD.

小儿神经发育障碍（NDD），包括小儿癫痫、自闭症谱系障碍和