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Investigating UBE3A as a driver gene in Duplication 15q syndrome

研究 UBE3A 作为 15q 重复综合征的驱动基因

基本信息

批准号：
10566815
负责人：
BENJAMIN D PHILPOT
金额：
$ 42.25万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566815
关键词：
Accounting Adolescent Adult Age Antisense Oligonucleotides Behavioral Biological Sciences Brain Cells Chromosome 15 Chromosome abnormality Chromosomes Clinical Trials Coupled Data Disease Dose Electrophysiology (science)Engineering Epilepsy Frequencies Functional disorder Future Gene Dosage Gene Expression Genes Genetic Human In Vitro Intervention Isodicentric Chromosome Lead Maps Modeling Mus Neonatal Neurodevelopmental Disorder Outcome Pathology Phenotype Physiological Population Proteins Seizures Severities Syndrome Testing Therapeutic Therapeutic Intervention Transgenes Transgenic Organisms UBE3A gene Work autism spectrum disorder candidate identification chromosome 15q duplication syndrome critical period design genomic locus in vivo interstitial knock-down mortality mouse model overexpression pharmacologic postnatal preclinical study primary endpoint prospective sudden unexpected death in epilepsy tool

项目摘要

PROJECT SUMMARY Maternal duplication of the chromosome 15q11-q13 locus (Dup15q syndrome) is a major genetic cause of autism spectrum disorder. UBE3A is contained within this genetic locus; compelling evidence suggests it is the main driver of Dup15q syndrome pathophysiology. Accordingly, the normalization of UBE3A levels might effectively treat the syndrome, but this has been difficult to test. To allow us to test this idea, we have generated conditional Ube3a-overexpression mice that have construct validity for the principal cytogenetic abnormalities underlying Dup15q syndrome: interstitial chromosome 15 duplication (1 extra copy of Ube3a) and isodicentric chromosome 15 (2 extra copies of Ube3a). Thus, our models will be valuable for determining the extent to which increases in UBE3A protein levels are necessary and sufficient to drive Dup15q-relevant pathophysiology. With these mice, we are also able to genetically normalize Ube3a expression at different ages, allowing us to identify the window during which normalization provides substantial therapeutic benefit. To advance an informed intervention strategy for Dup15q syndrome, we will use our new mouse models to (1) establish the behavioral and physiological consequences of UBE3A overexpression, (2) determine when normalization of UBE3A rescues pathophysiology, and (3) optimize an approach to appropriately knock down UBE3A and correct pathophysiology in Ube3a-overexpression mice.

项目概要染色体 15q11-q13 位点的母体重复（Dup15q 综合征）是导致自闭症谱系障碍。 UBE3A 包含在该基因位点内；令人信服的证据表明这是 Dup15q 综合征病理生理学的主要驱动因素。因此，UBE3A 水平的正常化可能有效治疗该综合征，但这一直难以测试。为了让我们测试这个想法，我们有产生了条件性 Ube3a 过表达小鼠，其对主要细胞遗传学具有构建有效性 Dup15q 综合征的异常：间质 15 号染色体重复（1 个额外的 Ube3a 拷贝）和等双着丝粒染色体 15（Ube3a 的 2 个额外拷贝）。因此，我们的模型对于确定 UBE3A 蛋白水平的增加对于驱动 Dup15q 相关是必要且充分的病理生理学。对于这些小鼠，我们还能够在不同的时间对 Ube3a 表达进行基因标准化。年龄，使我们能够确定正常化提供实质性治疗益处的窗口。到推进 Dup15q 综合征的知情干预策略，我们将使用我们的新小鼠模型来 (1) 确定 UBE3A 过度表达的行为和生理后果，(2) 确定何时 UBE3A 的正常化可挽救病理生理学，并且 (3) 优化适当敲除的方法 UBE3A 和 Ube3a 过度表达小鼠的正确病理生理学。