Molecular and Cellular Basis of Neurodevelopmental Disorders

神经发育障碍的分子和细胞基础

基本信息

批准号：
10347351
负责人：
Craig M Powell
金额：
$ 65.5万
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：
2020
资助国家：
美国
起止时间：
2020-03-10 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10347351
关键词：
16p11.2 Actins Adaptor Signaling Protein Address Affect Animal Genetics Animal Model Area Behavior Behavioral Behavioral Symptoms Binding Proteins Biochemistry Brain CUL3 gene Cell Culture Techniques Code Complex Copy Number Polymorphism DNA Sequence Alteration Data Databases Dendritic Spines Development Disease Disease model Drosophila genus Exhibits FDA approved Face Functional disorder Future Gene Expression Gene Proteins Genes Genetic Genetic Models Head Hela Cells Hippocampus (Brain)Human In Vitro Intellectual functioning disability Lead Light Link Macrocephaly Microcephaly Modeling Molecular Monomeric GTP-Binding Proteins Morphology Mus Mutation Nature Neurodevelopmental Disorder Neuronal Dysfunction Neurons PTEN gene Pathway interactions Patients Pharmacotherapy Phenotype Proteins Proteomics Publishing Recurrence Regulation Role Schizophrenia Signal Pathway Social Interaction Structure Synapses Synaptic Transmission Therapeutic Translating Ubiquitination Work Xenopus Zebrafish autism spectrum disorder base brain morphology brain size cell motility communication behavior conditional mutant exome sequencing experience gene function gene product innovation interest loss of function mutation mouse model mutant mutant mouse model neurodevelopment neurogenesis neuron development novel repetitive behavior synaptic function therapeutic target transcriptomics treatment strategy ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary/Abstract Neurodevelopmental disorders are common, debilitating disorders including autism, intellectual disability, and perhaps even schizophrenia. Recent genetic findings have identified mutations in multiple genes in various cellular pathways as genetic causes of neurodevelopmental disorders including autism spectrum disorders, intellectual disability, and others. This proposal will characterize novel and innovative genetic mouse models to delineate the function of these genes in the brain. Specifically, the proposal will focus on two genes implicated in either 16p11.2 deletion or autism, both of which are predicted to be involved in overlapping intra- neuronal signaling pathways and regulation of neuronal and synaptic function/development based on preliminary findings. In addition to identifying the neuronal function of these genes in the brain, these studies will identify potential therapeutic strategies for treatment of genetic forms of autism and intellectual disability and possibly other neurodevelopmental disorders. Progress to date is substantial in that two novel mutant mouse models relevant for neurodevelopmental disorders have been established and preliminary characterization of synaptic function, neuronal development, neuronal biochemistry, and neuronal morphology among other aspects of brain function has begun. Unbiased proteomic/transcriptomic approaches to identifying additional, novel downstream targets of these gene products in mammalian brain will generate new hypotheses anticipated to lead to additional potential therapeutic strategies.

项目摘要/摘要神经发育障碍是常见的，使人衰弱，包括自闭症，智力残疾和也许甚至精神分裂症。最近的遗传发现已经确定了各种基因的突变细胞途径是神经发育障碍的遗传原因，包括自闭症谱系障碍，智力残疾和其他人。该建议将表征新颖和创新的遗传小鼠模型描绘这些基因在大脑中的功能。具体而言，该提案将集中于两个基因与16p11.2删除或自闭症有关，预计这两者都参与了重叠 - 基于神经元信号通路以及基于神经元和突触功能/发育的调节初步发现。除了鉴定这些基因在大脑中的神经元功能外，这些研究将确定潜在的治疗策略来治疗遗传形式的自闭症和智力残疾还有其他神经发育障碍。到目前为止的进度是很大的，因为两个新型突变体已经建立了与神经发育障碍相关的鼠标模型和初步突触功能，神经元发育，神经元生化和神经元形态的表征大脑功能的其他方面已经开始。无偏的蛋白质组学/转录组方法识别这些基因产物在哺乳动物大脑中的其他新型下游靶标将产生新的预计会导致其他潜在治疗策略的假设。