Molecular mechanisms underlying vocal communication

声音交流的分子机制

基本信息

批准号：
10525242
负责人：
Maria Chahrour
金额：
$ 39.4万
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：
2019-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10525242
关键词：
Abbreviations Address Adult Affect Applied Genetics Biochemical Body Weights and Measures Brain Carboxylic Acids Child Clinical Co-Immunoprecipitations Cognition Cognitive Communication Complex Data Data Set Development Disease Enzymes Equilibrium Future Genes Genetic Genetic Diseases Genomics Goals Growth Health Hearing Human Human Genetics Immunoprecipitation Impairment Intellectual functioning disability Keto Acids Knock-out Knockout Mice Knowledge Laboratories Language Learning Measures Mediating Memory Metabolic Pathway Molecular Motor Mutation Neurodevelopmental Disorder Neurons Oxidoreductase Pathogenicity Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Physiological Process Proteins Proteomics Research Role Social Behavior Speech Syndrome Testing Ubiquitination Ultrasonics Validation Western Blotting Work autism spectrum disorder benzothiophene communication behavior conditional knockout conditioned fear effective therapy experimental study gene function genetic architecture in vivo inhibitor insight loss of function morris water maze mouse model muscle strength nerve stem cell neurobehavioral novel novel therapeutic intervention postnatal protein protein interaction social communication targeted treatment treatment strategy ubiquitin ligase ubiquitin-protein ligase vocalization

项目摘要

Project Summary The molecular pathways underlying cognition and vocal communication remain largely unknown. The genes and mechanisms governing these processes are disrupted in many neurodevelopmental disorders, including intellectual disability and autism spectrum disorder. The long-term goal of our laboratory is to study the normal function of genes disrupted in disorders with deficits in cognition, communication, and social behavior, to gain mechanistic understanding that can be leveraged for treatment opportunities. Mutations in the gene encoding the ubiquitin ligase UBE3B have been identified in patients with intellectual disability and lack of speech. The specific mechanism(s) that give rise to the neurodevelopmental phenotypes and the UBE3B substrates that mediate these mechanisms are completely unknown. Our preliminary studies suggest a role for UBE3B in brain development and vocalization. In addition, we identified the branched-chain a-ketoacid dehydrogenase kinase (BCKDK) as a substrate for UBE3B. We propose to dissect the molecular networks regulated by UBE3B and its role in mediating vocalization, through the following three specific aims: 1) Determine the role of UBE3B in vocalization; 2) Identify the neuronal substrates of UBE3B through quantitative proteomics and biochemical validation experiments; 3) Rescue the neurodevelopmental phenotypes associated with UBE3B loss of function by targeting its substrate BCKDK. Together, these aims will identify the molecular networks regulated by UBE3B that may underlie the lack of speech and other neurodevelopmental phenotypes observed in patients with UBE3B disruption. Successful completion of the proposed aims will provide new insights into pathways regulating vocalization, increase our knowledge of the specific pathogenic mechanism underlying neurodevelopmental disorders with communication deficits, and examine new therapeutic approaches.

项目摘要认知和声音交流的分子途径在很大程度上未知。基因和在许多神经发育障碍中，包括这些过程的机制被破坏了，包括智力残疾和自闭症谱系障碍。我们实验室的长期目标是研究正常在认知，沟通和社会行为方面缺陷的疾病中破坏的基因的功能，以获得机械理解可以利用治疗机会。基因编码中的突变在智力残疾和缺乏言语的患者中，已经确定了泛素连接酶UBE3B。这引起神经发育表型和UBE3B底物的特定机制介导这些机制是完全未知的。我们的初步研究表明ube3b在大脑中的作用发展和发声。此外，我们确定了分支链A-酮酸脱氢酶激酶激酶（BCKDK）作为UBE3B的基板。我们建议剖析UBE3B调节的分子网络及其在调解发声中的作用，通过以下三个具体目的：1）确定 ube3b发声； 2）通过定量蛋白质组学和生化验证实验； 3）营救与UBE3B损失相关的神经发育表型通过靶向其底物BCKDK来实现功能。这些目的共同确定了受调节的分子网络 ube3b可能是患者缺乏语音和其他神经发育表型的基础与UBE3B中断有关。成功完成拟议的目标将为途径提供新的见解调节发声，增加我们对依据特定病原机制的了解神经发育障碍患有沟通缺陷，并检查新的治疗方法。