Molecular Mechanisms of UBE3A Mediated Synapse Development in Angelman Syndrome

UBE3A介导天使综合征突触发育的分子机制

• 批准号: 8759291
• 负责人: SETH S MARGOLIS
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-16 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759291
• 关键词: Address; Affect; Amino Acid Sequence; Angelman Syndrome; Autistic Disorder; Behavior; Behavioral; Biogenesis; Biological Assay; Brain; Brain region; Chromosome abnormality; Cognition Disorders; Cognitive deficits; Data; Defect; Dendritic Spines; Development; Disease; Etiology; Excitatory Synapse; Functional disorder; Gene Mutation; Genes; Genetic; Goals; Guanine Nucleotide Exchange Factors; High Prevalence; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Individual; Learning; Link; Location; Mediating; Molecular; Mus; Mutant Strains Mice; Mutation; Nervous system structure; Neuraxis; Neurodevelopmental Disorder; Neuronal Dysfunction; Neurons; Outcome; Pathology; Patients; Peptide Sequence Determination; Phenotype; Protein Array; Proteins; Proteomics; Publishing; Regulation; Research; Research Design; Role; Signal Transduction; Structure; Synapses; Testing; Time; Ubiquitin-Protein Ligase Complexes; Ubiquitination; Viral; Virus; Work; base; brain morphology; cofactor; cognitive function; improved; in vivo; innovation; insight; neurodevelopment; neuron development; novel; novel strategies; public health relevance; relating to nervous system; research study; small hairpin RNA; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): This new application focuses on the determination of the mechanism by which loss of UBE3A leads to synaptic dysfunction. Based on extensive prior findings, our overall hypothesis is that UBE3A operates to regulate levels of substrate proteins important for neural development, and that disruption of UBE3A activity leads to inappropriately high levels of these substrates, causing the neuronal dysfunctions observed in Angelman Syndrome (AS). The proposed studies are designed to provide improved understanding of the link between aberrations of UBE3A signaling and AS phenotypes. As a long-term goal, our findings will aid in the development of novel approaches for pharmacological manipulation of mis-regulated UBE3A substrates, resulting in new and innovative approaches for the treatment of AS, and possibly other non-syndromic autistic disorders. Specifically: Aim 1. To determine the contribution of elevated Ephexin5 levels to AS- associated phenotypes, to test the hypothesis that elevated Ephexin5 expression in Ube3a mutant mice result in AS-associated synaptic and behavioral phenotypes; Aim 2. To determine the molecular mechanisms controlling UBE3A-mediated Ephexin5 ubiquitination, to test the hypothesis that distinct protein sequences on Ephexin5 and additional cofactors spatially and temporally control UBE3A mediated ubiquitination of Ephexin5; Aim 3. To identify neural substrates of UBE3A, to test the hypothesis that additional UBE3A substrates participate in the etiology of AS.

描述（由申请人提供）：该新申请专注于确定UBE 3A缺失导致突触功能障碍的机制。基于广泛的先前发现，我们的总体假设是UBE 3A调节对神经发育重要的底物蛋白的水平，并且UBE 3A活性的破坏导致这些底物的不适当的高水平，导致在Angelman综合征（AS）中观察到的神经元功能障碍。拟议的研究旨在更好地了解UBE 3A信号传导异常与AS表型之间的联系。作为一个长期目标，我们的研究结果将有助于开发新的方法，用于药物操纵错误调节的UBE 3A底物，从而产生新的和创新的方法来治疗AS，以及可能的其他非综合征性自闭症障碍。具体而言：目标1。为了确定升高的Ephexin 5水平对AS相关表型的贡献，以测试Ube 3a突变小鼠中升高的Ephexin 5表达导致AS相关突触和行为表型的假设;目的2.确定控制UBE 3A介导的Ephexin 5泛素化的分子机制，以检验Ephexin 5上的不同蛋白质序列和另外的辅因子在空间和时间上控制UBE 3A介导的Ephexin 5泛素化的假设;目的3.鉴定UBE 3A的神经底物，以检验其他UBE 3A底物参与AS病因学的假设。