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GABA-A Receptor Alpha 1 Subunit Mutations and Epilepsy

GABA-A 受体 Alpha 1 亚基突变与癫痫

基本信息

批准号：
8434130
负责人：
MARTIN J GALLAGHER
金额：
$ 32.27万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8434130
关键词：
Absence Epilepsy Acoustics Affect Brain Cells Chemicals Comorbidity Development Disease Disinhibition Epilepsy Etiology GABA-A Receptor Generalized Epilepsy Genes Genetic Goals Juvenile Myoclonic Epilepsy Knock-in Mouse Knock-out Learning Left Ligand Binding Link Medical Messenger RNA Motor Activity Mutant Strains Mice Mutate Mutation Neurons Nonsense-Mediated Decay Pharmaceutical Preparations Phenotype Physiology Play Polygenic Traits Prevention strategy Protein Subunits Radiolabeled Relative (related person)Residual state Resistance Role Seizures Sensory Slice Surface Symptoms Synapses Syndrome Testing Time Tissues Work base brain tissue functional loss induced pluripotent stem cell mouse model nervous system disorder neurobehavioral neuropsychiatry novel protein expression public health relevance radiotracer receptor receptor expression research study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Mutations of the GABA--A receptor (GABAAR) alpha 1 subunit have recently been associated with idiopathic generalized epilepsy (IGE) syndromes. Neurons increase the expression of the alpha 1 subunit at the times in development when the symptoms of the IGE syndromes typically arise. Our long term goal is to understand how these mutations disrupt GABAAR expression and physiology at specific times in development in order to provide a mechanistic basis for the development of new treatment and prevention strategies for these epilepsy syndromes and their co-morbid conditions. The hypotheses to be tested are: 1) because 11 subunit expression increases throughout development, GABRA1 epilepsy mutations will reduce total GABAAR subunit protein and produce neurons with smaller IPSC amplitudes relative to wild type neurons by P19, 2) the GABRA1 epilepsy mutations will increase the relative surface expression of 12-3 subunits in P19 neurons from mutant mice due to an increased 12-3 to 11 subunit ratio, and 3) because 11 subunit expression increases during development, mutant mice will demonstrate more severe epileptic and neurobehavioral phenotypes at P19 than at P12. The specific aims are: 1) determine the effects of the knock-out and knock-in mutations on total GABAAR expression and IPSC amplitudes throughout development, 2) determine the effects of knock-out and knock-in mutations on expression of 11-5 subunits throughout development and the relationship of 11-5 subunit protein abundance to incorporation in GABAAR and 3) determine the effects of the knock-out and knock-in mutations on the development of the epilepsy and neurobehavioral phenotypes.

描述（由申请人提供）：GABA- A受体(GABAAR) α 1亚基突变最近与特发性广泛性癫痫（IGE）综合征相关。在发育过程中，当IGE综合征的症状通常出现时，神经元增加α 1亚基的表达。我们的长期目标是了解这些突变如何在特定的发育时期破坏GABAAR的表达和生理，以便为开发针对这些癫痫综合征及其合并症的新治疗和预防策略提供机制基础。需要测试的假设有：1)由于11个亚基的表达在整个发育过程中增加，GABRA1癫痫突变会减少GABAAR亚基蛋白总量，产生相对于P19野生型神经元IPSC振幅较小的神经元；2)GABRA1癫痫突变会增加突变小鼠P19神经元中12-3个亚基的相对表面表达，因为12-3与11个亚基的比例增加；3)因为11个亚基的表达在发育过程中增加。突变小鼠在P19位点比P12位点表现出更严重的癫痫和神经行为表型。具体目的是：1)确定敲除和敲入突变对整个发育过程中GABAAR总表达和IPSC振幅的影响；2)确定敲除和敲入突变对整个发育过程中11-5亚基表达的影响以及11-5亚基蛋白丰度与GABAAR掺入的关系；3)确定敲除和敲入突变对癫痫和神经行为表型发展的影响。