The role of UBE3A in gliopathic seizures

UBE3A 在胶质病性癫痫发作中的作用

基本信息

批准号：
10674705
负责人：
LAWRENCE T REITER
金额：
$ 39.79万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674705
关键词：
15q Affect Alleles Anticonvulsants Antiepileptic Agents Autopsy Behavior Behavioral Brain Buffers Calcium Cephalic Country Defect Development Disease Drosophila genus Drosophila melanogaster Epilepsy Etiology GABA Receptor Goals Homeostasis Homologous Gene Homologous Protein Impairment Individual Intervention Knowledge Laboratories Learning Mammals Mediating Modeling Molecular Mus Neuroglia Neurons Paracrine Communication Pathway interactions Persons Pharmaceutical Preparations Phenotype Potassium Predisposition Process Proteins Proteomics Receptor Gene Reproducibility Research Role Seizures Signal Transduction Synapses Syndrome Temperature Therapeutic Time UBE3A gene Work cell type cellular pathology chromosome 15q duplication syndrome design dietary epidemiology study experimental study extracellular fly insight molecular pathology mouse model neurogenetics neurotransmission new therapeutic target overexpression small molecule therapeutics ubiquitin-protein ligase

项目摘要

As many as ~3 million individuals suffer from epileptic seizures in the US alone. Although some forms of epilepsy respond quite well to anti-seizure medications, a substantial portion of individuals suffering from epilepsy do not respond well to medication or dietary treatments. One way to investigate the underlying molecular and cellular pathology of seizure disorder is by studying a genetically defined syndrome where epilepsy is a prominent feature. Approximately 25-50% of individuals with Duplication 15q syndrome (Dup15q) suffer from difficult to control seizures. The prevailing hypotheses to explain seizures in Dup15q are maternal specific neuronal elevation of the ubiquitin E3 ligase UBE3A and/or duplication of a cluster of GABA receptor genes located adjacent to UBE3A at 15q11.2-q13.1. Studies using the fruit fly, Drosophila melanogaster, from our laboratory indicates that these seizures may be caused by elevated levels of UBE3A in glia, not neurons as previously proposed. The premise for this proposal is that seizures are caused by elevated levels of the UBE3A protein in glia, not neurons, providing not only a pathway to molecular mechanism for Dup15q related epilepsy, but also a paradigm shift, directly implicating glial cells in the etiology of seizures. The experiments outlined in this proposal are designed to investigate the developmental timing and molecular changes in glial cells over-expressing Dube3a and to reveal how these changes are recapitulated in a new mouse model we developed that expresses Ube3a in glial cells. Everything we learn from these studies in flies will be directly disseminated to a team of seizure experts who work at the Duplication 15q centers of excellence throughout the country. The identification of new therapeutic targets for Dup15q epilepsy may also provide new treatment options to individuals who are pharmacoresistant to current anti-epileptics.

仅在美国，就有多达300万人患有癫痫发作。虽然某些形式的癫痫对抗性药物的反应很好，大部分患有癫痫病的人没有对药物或饮食疗法的反应很好。研究基础分子和细胞的一种方法癫痫发作障碍的病理是研究遗传定义的综合征，其中癫痫是重要的特征。大约25-50％的复制15q综合征（DUP15Q）的人难以控制癫痫发作。在DUP15Q中解释癫痫发作的主要假设是母亲特异性的神经元升高泛素E3连接酶UBE3A和/或与Ube3a相邻的GABA受体基因的复制在15Q11.2-Q13.1。使用果蝇，果蝇Melanogaster的研究，我们的实验室表明这些癫痫发作可能是由于胶质细胞中的UBE3A水平升高而不是先前提出的神经元引起的。前提因为该提议是癫痫发作是由神经胶质中的Ube3a蛋白水平升高而不是神经元引起的不仅为DUP15Q相关癫痫的分子机制提供了一种途径，而且还提供了范式转移的途径直接暗示神经胶质细胞在癫痫病的病因中。该提案中概述的实验是设计的研究过表达dube3a的神经胶质细胞中的发育时机和分子变化，在我们开发的新鼠标模型中揭示这些变化是如何概括的细胞。我们从这些研究中学到的一切将直接传播给一组癫痫发作专家在全国重复15q卓越中心工作的人。新的识别 DUP15Q癫痫的治疗靶标也可能为个人提供新的治疗选择药物对当前的抗癫痫药。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.

DOI：
10.1016/j.cell.2022.08.022
发表时间：
2022-10-13
期刊：
CELL
影响因子：
64.5
作者：
Davenport, Christopher M.;Teubner, Brett J. W.;Han, Seung Baek;Patton, Mary H.;Eom, Tae-Yeon;Garic, Dusan;Lansdell, Benjamin J.;Shirinifard, Abbas;Chang, Ti-Cheng;Klein, Jonathon;Pruett-Miller, Shondra M.;Blundon, Jay A.;Zakharenko, Stanislav S.
通讯作者：
Zakharenko, Stanislav S.