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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.

项目概要/摘要神经发育障碍是常见的使人衰弱的疾病，包括自闭症、智力障碍和甚至可能患有精神分裂症。最近的遗传学研究发现，多种基因中存在突变。细胞通路作为神经发育障碍（包括自闭症谱系障碍）的遗传原因，智力障碍等。该提案将表征新颖和创新的基因小鼠模型描述这些基因在大脑中的功能。具体来说，该提案将重点关注两个基因与 16p11.2 缺失或自闭症有关，预计这两者都与重叠的内部相关神经元信号通路以及神经元和突触功能/发育的调节初步调查结果。除了确定大脑中这些基因的神经元功能外，这些研究将确定治疗遗传形式自闭症和智力障碍的潜在治疗策略以及可能的其他神经发育障碍。迄今为止的进展是巨大的，因为这两个新的突变体神经发育障碍相关小鼠模型已建立并初步突触功能、神经元发育、神经元生物化学和神经元形态的表征大脑功能的其他方面已经开始。无偏见的蛋白质组学/转录组学方法来识别此外，哺乳动物大脑中这些基因产物的新下游靶标将产生新的预计将产生额外的潜在治疗策略的假设。