Investigating the role of BCKDK in neurodevelopmental disorders through a novel mouse model

通过新型小鼠模型研究 BCKDK 在神经发育障碍中的作用

基本信息

批准号：
9812785
负责人：
Maria Chahrour
金额：
$ 16.2万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-23 至 2021-08-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9812785
关键词：
16p11.2 Affect Animal Model Brain Branched-Chain Amino Acids Chromosomes Clinical Cognitive Communities Complex Data Development Developmental Delay Disorders Disease Economic Burden Epilepsy Funding Opportunities Genes Genetic Genome Genomics Goals Growth Health Human Human Genetics Impaired cognition Impairment Intellectual functioning disability Knockout Mice Language Learning Link Measures Mediating Memory Metabolic Pathway Microcephaly Molecular Morphogenesis Muscle hypotonia Mutation Neurodevelopmental Disorder Neurons Pathogenicity Patients Phenotype Phosphotransferases Play Protein Kinase Reagent Research Research Project Grants Resources Role Social Behavior Speech Syndrome Testing Time Tissues Transgenic Mice UBE3A gene Ultrasonics amino acid metabolism autism spectrum disorder branched chain alpha ketoacid dehydrogenase conditioned fear effective therapy evidence base gene function genetic architecture in vivo loss of function mutation morris water maze mouse model muscle strength neurobehavioral neuropsychiatry novel overexpression programs severe intellectual disability social targeted treatment ubiquitin-protein ligase vocalization

项目摘要

Project Summary Neurodevelopmental disorders (NDDs) affecting cognitive and social abilities are a phenotypically and genetically heterogeneous group of conditions. Understanding the molecular mechanisms underlying these disorders is crucial for the development of targeted therapies. Loss-of-function mutations in the gene BCKDK, encoding the branched-chain a-ketoacid dehydrogenase kinase, result in autism spectrum disorder (ASD) and epilepsy. Conversely, duplications of chromosome 16p11.2 spanning the BCKDK locus have been identified in patients with a spectrum of neurodevelopmental phenotypes, including developmental delay, speech and language abnormalities, intellectual disability, ASD, and microcephaly. However, it is not known whether the neurodevelopmental phenotypes arise due to an increased copy of BCKDK or how BCKDK overexpression mediates these phenotypes. The goal of this proposal is to generate a transgenic mouse model overexpressing BCKDK, and to characterize the resulting neurobehavioral phenotypes. Our proposal will develop the first mouse model of BCKDK overexpression and test, for the first time, the link between BCKDK overexpression and NDDs. Results from our studies will “illuminate” an understudied protein kinase, BCKDK, by providing animal model- based evidence for disease relevance and generating reagents and data for the scientific community.

项目摘要影响认知和社会能力的神经发育障碍（NDDS）是表型和遗传上异质的条件群。了解这些分子机制疾病对于靶向疗法的发展至关重要。基因BCKDK的功能丧失突变，编码分支链A-酮酸脱氢酶激酶，导致自闭症谱系障碍（ASD）和癫痫。相反，跨越BCKDK基因座的染色体16p11.2的重复已在具有多种神经发育表型的患者，包括发育延迟，言语和语言异常，智力残疾，ASD和小头畸形。但是，尚不知道是否神经发育表型由于BCKDK的副本增加或BCKDK过表达而产生介导这些表型。该建议的目的是生成过表达的转基因鼠标模型 BCKDK，并表征所得的神经行为表型。我们的建议将发展第一只鼠标 BCKDK过表达和测试的模型首次是BCKDK过表达与NDD之间的链接。我们的研究结果将通过提供动物模型来“阐明”一种理解的蛋白激酶BCKDK。基于疾病相关性的证据，并为科学界生成试剂和数据。