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

• 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
• 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

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），包括儿科癫痫，自闭症谱系障碍和 智力残疾是发病率的主要来源，但我们的治疗选择仍然有限。 开发新的NDD疗法将需要对正常和 脑发育异常。该提案的重点是响应于 神经元活性，这是正常神经发育和持续神经元可塑性的基础 一生。 FOS是与远端增强子元素结合的主要活动依赖性转录因子和 以细胞类型的方式调节下游活动依赖性遗传程序以促进钥匙 过程，包括突触修剪和发育中大脑中抑制作用的募集。尽管它在 关键的发展过程，我们不了解FOS如何针对细胞类型的特定目标。 结合位点，也不是这些位点的遗传变异如何影响神经发育和神经元功能。 有趣的是，FOS已显示与BAF染色质重塑复合物进行物理相互作用，并且是 这种相互作用可能对FOS函数至关重要。许多BAF亚基，最常见的Arid1b，是 在人类NDD中实施，但是BAF复合物是否调节神经元活动依赖性遗传 程序，以及这如何构成与BAF复杂相关NDD的各个方面，以前是出乎意料的。研究 在此提案中，将通过以下方式解决这些知识的差距 人类基因组的位置； （b）评估NDD VS个体的这些位点的人类遗传变异 控件； （c）确定BAF复合扰动对神经元活性依赖性遗传的影响 在体外和体内程序。总体而言，这项工作将使人们更深入地了解活动依赖性通用 程序有助于NDD发病机理。另外，通过识别特定活性调节的基因和 这些实验可以突出显示FOS和BAF复合物的下游途径。 NDD的新型治疗靶标。 这项研究是旨在以Trowbridge博士为基础的五年职业发展计划的基础 分子神经科学，小儿神经病学/癫痫和神经遗传学的背景，通过为她提供 对人类测序数据分析的额外培训，NDD的体外和体内模型的使用以及接下来的培训 生成测序技术。她的主要导师Mike Greenberg博士和她的科学咨询 委员会，博士。 Annapurna Poduri和Chris Walsh将在这些领域提供指导，并提供指导 在转化神经科学研究的严格和道德行为中。拟议的培训计划将 位置Trowbridge博士，以启动她作为临床科学家的独立职业，专注于了解 活性依赖性遗传程序在NDD中的作用。