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The Contribution of Microglial MEF2C to Brain Development

小胶质细胞 MEF2C 对大脑发育的贡献

基本信息

批准号：
10544181
负责人：
Nicole Gabriele Coufal
金额：
$ 40.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544181
关键词：
Affect Aging Alleles Anti-Inflammatory Agents Behavioral Behavioral Assay Biological Models Brain Cells Cerebrum Child Childhood Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Communication Complement Data Data Set Dependence Development Developmental Disabilities Diagnosis Disease Drug Screening Drug Utilization Engraftment Enhancers Environment Epigenetic Process Functional disorder Gene Expression Genes Genetic Transcription Genomics Goals Heterozygote Human Immunity Impairment In Vitro Inflammation Mediators Inflammatory Intellectual functioning disability Interleukin-10 Interleukin-6 Knowledge Life Link Macrophage Maps Measurement Measures Mediating Methods Microglia Mission Modeling Mus Mutation Neurodevelopmental Deficit Neurodevelopmental Disorder Neurons Organoids Outcome Pathogenesis Pathology Pathway interactions Phagocytosis Pharmacological Treatment Phenotype Prosencephalon Public Health Regulation Reporting Research Role Science Social Behavior Social Interaction Stimulus Synapses Syndrome System Techniques Testing Therapeutic Thick United States United States National Institutes of Health autism spectrum disorder autistic children behavioral phenotyping cell type chromatin immunoprecipitation density disability effective therapy gene network glial cell development human data improved outcome in vivo in vivo Model induced pluripotent stem cell insight microdeletion migration motor behavior myocyte-specific enhancer-binding factor 2 myocyte-specific enhancer-binding-factor 2C nerve stem cell neurodevelopment new therapeutic target novel pre-clinical response social social deficits stem cell model synaptic pruning therapeutic target transcription factor transcriptomics

项目摘要

Summary/Abstract Intellectual disability and autism spectrum disorders are devastating disorders thought to arise from a combination of synaptic dysfunction and altered neural progenitor modulation for which there are no effective treatments. Mutations or deletions in one allele of myocyte enhancer factor 2C (MEF2C) result in MEF2C Haploinsufficiency Syndrome (MHS), a disorder characterized by a severe phenotype with intellectual disability, repetitive motor behaviors, and difficulties with communication and social interaction on the autism spectrum. We have found that MEF2C is highly expressed in human microglia during neurodevelopment and have identified MEF2C as a core transcription factor involved in the microglial cell fate. Furthermore, MEF2C expression is regulated by the brain environment and decreases during aging. Microglia have not been extensively investigated in the pathogenesis of neurodevelopmental disorders, but there is increasing evidence for their impact on brain development suggesting they may contribute to especially the social and behavioral deficits in autism. The central hypothesis is that microglial MEF2C has a crucial role in human brain development and contributes to neurodevelopmental disorders including intellectual disability and autism pathogenesis and the resulting behavioral phenotype. We will utilize novel in vitro and in vivo methods to ascertain the role of microglial MEF2C in brain development including synapse retention and pruning, modulation of the neural progenitor pool, and microglial development. The project goal is to test the hypothesis that MEF2C specifically in human microglia contributes to brain development and reduced expression contributes to neurodevelopmental deficits found in intellectual disability and autism. Delineating MEF2C transcriptional and environmental targets using epigenetic techniques will yield novel insight into human microglial transcriptional networks and expand on our knowledge of autism associated genes with the potential to yield novel therapeutic targets. The long-term goal is to generate and validate methods using human microglia specifically which can be utilized for drug screening and to generate preclinical data in order to ultimately identify novel potential therapeutic targets to improve the outcomes for children with autism.

总结/摘要智力残疾和自闭症谱系障碍是毁灭性的疾病，被认为是由以下因素的组合引起的：突触功能障碍和改变的神经祖细胞调节，对此没有有效的治疗方法。突变或肌细胞增强因子2C（MEF 2C）的一个等位基因缺失导致MEF 2C单倍不足综合征（MHS），一种以智力残疾、重复性运动行为和运动障碍的严重表型为特征的疾病，交流和社会互动的能力。我们已经发现MEF 2C在人类中高度表达， MEF 2C是神经发育过程中小胶质细胞的一种重要的转录因子，并且已经鉴定出MEF 2C是参与小胶质细胞分化的核心转录因子。细胞命运此外，MEF 2C的表达受大脑环境的调节，并在衰老过程中减少。小胶质在神经发育障碍的发病机制中尚未进行广泛的研究，但有越来越多的证据表明，因为它们对大脑发育的影响，这表明它们可能导致特别是社会和行为缺陷，自闭症核心假设是小胶质细胞MEF 2C在人类大脑发育中起着至关重要的作用，神经发育障碍，包括智力残疾和自闭症的发病机制，以及由此产生的行为表型我们将利用新的体外和体内方法来确定小胶质细胞MEF 2C在脑中的作用，发育，包括突触保留和修剪，神经祖细胞库的调节，和小胶质细胞发展该项目的目标是测试MEF 2C特异性地在人类小胶质细胞中有助于大脑发育的假设。发育和减少的表达有助于在智力残疾和自闭症中发现的神经发育缺陷。使用表观遗传学技术描绘MEF 2C转录和环境靶点将产生新的见解，人类小胶质细胞转录网络，并扩大了我们对自闭症相关基因的了解，产生新的治疗靶点。长期目标是专门利用人类小胶质细胞生成和验证方法其可用于药物筛选并产生临床前数据，以最终确定新的潜在的治疗目标，以改善自闭症儿童的结果。