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Elucidating the role of the E3 ubiquitin ligase UBE3B in neuronal activity

阐明 E3 泛素连接酶 UBE3B 在神经元活动中的作用

基本信息

批准号：
10703223
负责人：
Shayal Vashisth
金额：
$ 3.9万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10703223
关键词：
Acute Affect Amino Acids Antibodies Biochemical Brain Cell Culture Techniques Cells Child Clinical Co-Immunoprecipitations Collection Communication Complex Data Defect Development Electrophysiology (science)Environment Etiology Exhibits Fellowship Foundations Frequencies Genes Genetic Genetic Heterogeneity Goals Heritability Immunoprecipitation Impaired cognition Individual Intellectual functioning disability Knockout Mice Knowledge Lead Learning Length Literature Long-Term Potentiation Mass Spectrum Analysis Mediating Medical center Memory Mentorship Modification Molecular Morphogenesis Mus Mutation Neurodevelopmental Disorder Neurons Outcome Study Patch-Clamp Techniques Pathogenicity Pathology Pathway interactions Patients Phenotype Physiologic pulse Polyubiquitin Post-Translational Protein Processing Predisposition Procedures Property Protein Analysis Proteins Proteomics Regulation Research Research Personnel Role Signal Transduction Site Slice Social Interaction Speech Stable Isotope Labeling Synaptic plasticity Syndrome Training Ubiquitin Ubiquitination Ultrasonics Vertebral column Western Blotting Wild Type Mouse autism spectrum disorder comparison control conditional knockout density experimental study hippocampal pyramidal neuron human disease insight mouse model nestin protein neurodevelopment postsynaptic protein protein interaction protein purification repetitive behavior skills social social skills synaptic function targeted treatment therapeutic development ubiquitin-protein ligase vocalization

项目摘要

Project Summary Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects 1 in 54 children and exhibits significant phenotypic and genetic heterogeneity. Mutations in UBE3B, which encodes an E3 ubiquitin ligase, have been identified in patients presenting with intellectual disability, lack of speech, and ASD. The specific mechanism through which disruption of UBE3B, and subsequent dysregulation of its substrates, leads to neurodevelopmental abnormalities is unknown. Our group has previously shown that a Ube3b constitutive knockout mouse model exhibits a complete loss of vocalization and defects in nest building, as well as reduced dendritic complexity, length, and spine density. In this proposal, I will investigate the neuronal function of UBE3B by characterizing changes in neuronal activity following loss of UBE3B and identifying its neuronal substrates. I will apply complimentary electrophysiological and biochemical approaches using a brain-specific conditional Ube3b knockout mouse model (cKOnestin). I will characterize the electrophysiological properties of cortical neurons from cKOnestin mice, by evaluating their basal properties, including intrinsic excitability and rheobase current, and both short-term and long-term synaptic plasticity. Furthermore, I will identify the neuronal substrates of UBE3B through analysis of protein levels, protein-protein interactions, and ubiquitination status. I will also assess the UBE3B-mediated modifications of substrates, including the site of ubiquitination and the ubiquitin chain topology. Successful completion of the proposed aims will provide new insights into the interplay of ubiquitin signaling and neurodevelopment, as well as advance our knowledge of the specific pathogenic mechanisms underlying neurodevelopmental disorders. The exceptional research environment at UT Southwestern Medical Center, combined with the collective expertise of the mentorship team, will provide excellent training. Goals for this fellowship training include becoming knowledgeable in the relevant literature and attaining proficiency in both experimental procedures and communicating scientific information to varied audiences. The skills obtained through these goals will build the foundation for an independent and successful lead investigator in scientific research.

项目总结