GABA (A) Receptor Subunit Regulation in Epileptogenesis

GABA (A) 受体亚基在癫痫发生中的调节

• 批准号: 7730222
• 负责人: Amy R. Brooks-Kayal
• 金额: $ 12.4万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730222
• 关键词: Adult; Affect; Age; Animal Model; Animals; Antiepileptogenic; Automobile Driving; Binding; Bioinformatics; Biological Assay; Brain; Chimeric Proteins; Code; Collection; Complex; Consensus; Cyclic AMP-Responsive DNA-Binding Protein; Cytoplasmic Granules; Data; Development; Disease; Dominant-Negative Mutation; Epilepsy; Epileptogenesis; Family; Family member; GABA-A Receptor; Gene Expression; Gene Transfer; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Health; Hippocampus (Brain); Human; Laboratories; Mediating; Messenger RNA; Modeling; Mutate; Nature; Neurons; Neurotransmitter Receptor; Pathway interactions; Pharmacology; Play; Prevention therapy; Process; Prosencephalon; Protein Family; Proteins; Proteomics; Range; Rattus; Receptor Gene; Regulation; Regulatory Pathway; Repression; Role; Seizures; Signal Pathway; Signal Transduction; Site; Status Epilepticus; Stimulus; System; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Therapeutic; Viral; chromatin immunoprecipitation; dentate gyrus; gene delivery system; in vivo; member; neurotransmission; novel therapeutics; promoter; receptor; receptor binding; therapeutic target; transcription factor; viral gene delivery

DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is the most common form of epilepsy and is frequently medically intractable. There is abundant evidence that abnormalities in inhibitory neurotransmission play an important role in TLE. GABAA receptors (GABARs) are the most abundant inhibitory neurotransmitter receptors in forebrain, however, relatively little is known regarding regulation of their expression either in health or in disease. We have demonstrated long-term changes in expression of GABAR subunits, including decreases in the a1 subunit, in hippocampal dentate granule neurons (DGNs) following status epilepticus (SE) in adult rats, that are associated with marked changes in receptor pharmacology and function. Further, changes in a1 are highly dependent on the age at which SE occurs, and vary inversely with the likelihood of subsequent epilepsy development. In addition, we find that enhancing a1 levels using viral mediated gene transfer inhibits development of epilepsy after SE. These findings suggest that diminished a1 levels in DGN may contribute to epileptogenesis and that elevated a1 levels could be protective. To utilize this therapeutic potential, however, requires an understanding of how GABAR a1 subunit expression is regulated. We therefore propose to investigate potential regulatory mechanisms that control GABAR a1 gene expression. We will examine the role of two identified candidate signaling pathways, the cAMP response element binding protein (CREB) pathway and the glucocorticoid receptor pathway, in regulating GABAR a1 subunit expression following SE. Further, using a combination of bioinformatics and proteomics we will perform a screen for other transcription factors that show enhanced interaction with the a1 promoter after SE. The proposed studies are expected to elucidate how a1 expression is regulated and how this regulation is altered during epileptogenesis. Results of these studies should facilitate development of new therapies for the prevention or cure of epilepsy by identifying potential new therapeutic targets that specifically target regulation of GABAR subunit gene expression.

描述（由申请人提供）：颞叶癫痫 (TLE) 是最常见的癫痫形式，并且通常在医学上难以治愈。大量证据表明抑制性神经传递异常在 TLE 中发挥重要作用。 GABAA 受体 (GABAR) 是前脑中最丰富的抑制性神经递质受体，然而，人们对其在健康或疾病中的表达调节知之甚少。我们已经证明，成年大鼠癫痫持续状态（SE）后海马齿状颗粒神经元（DGN）中 GABAR 亚基表达的长期变化，包括 a1 亚基的减少，这与受体药理学和功能的显着变化相关。此外，a1 的变化高度依赖于 SE 发生的年龄，并且与随后发生癫痫的可能性成反比。此外，我们发现使用病毒介导的基因转移提高 a1 水平可以抑制 SE 后癫痫的发展。这些发现表明，DGN 中 a1 水平降低可能导致癫痫发生，而 a1 水平升高可能具有保护作用。然而，要利用这种治疗潜力，需要了解 GABAR a1 亚基表达是如何调节的。因此，我们建议研究控制 GABAR a1 基因表达的潜在调控机制。我们将研究两个已确定的候选信号通路，cAMP 反应元件结合蛋白 (CREB) 通路和糖皮质激素受体通路，在 SE 后调节 GABAR a1 亚基表达中的作用。此外，结合生物信息学和蛋白质组学，我们将筛选其他转录因子，这些转录因子在 SE 后显示与 a1 启动子的相互作用增强。拟议的研究有望阐明 a1 表达是如何调节的，以及这种调节在癫痫发生过程中是如何改变的。这些研究的结果应通过确定专门针对 GABAR 亚基基因表达调节的潜在新治疗靶点，促进预防或治疗癫痫的新疗法的开发。