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: 7032192
• 负责人: Amy R. Brooks-Kayal
• 金额: $ 38.33万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 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/7032192
• 关键词: GABA receptor; adeno associated virus group; biological signal transduction; cAMP response element binding protein; chromatin immunoprecipitation; corticosteroid receptors; generalized seizures; genetic promoter element; genetic regulation; intermolecular interaction; laboratory rat; neurogenetics; neuropathology; partial seizure; proteomics; receptor binding; receptor expression; surface enhanced laser desorption ionization; temporal lobe /cortex disorder; tissue /cell culture; transfection /expression vector

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）是癫痫的最常见形式，通常在医学上棘手。有大量证据表明，抑制性神经传递的异常在TLE中起着重要作用。 GABAA受体（GABAR）是前脑中最丰富的抑制性神经递质受体，但是，关于其在健康或疾病中的表达的调节，相对较少。我们已经证明了GABAR亚基表达的长期变化，包括A1亚基的降低，在成年大鼠状态性癫痫症（SE）之后，海马齿状颗粒神经元（DGNS）与受体药理学和功能的明显变化有关。此外，A1的变化高度依赖于SE发生的年龄，并且与随后的癫痫发育的可能性相反。此外，我们发现使用病毒介导的基因转移促进A1水平会抑制SE后癫痫的发展。这些发现表明，DGN中的A1水平降低可能有助于癫痫发生，并且升高的A1水平可能具有保护性。但是，要利用这种治疗潜力，需要了解如何调节Gabar A1亚基表达。因此，我们建议研究控制GABAR A1基因表达的潜在调节机制。我们将研究两个已鉴定的候选信号通路，CAMP响应元件结合蛋白（CREB）途径和糖皮质激素受体途径的作用，在调节SE后调节Gabar A1亚基表达中的作用。此外，使用生物信息学和蛋白质组学的组合，我们将对其他转录因子进行屏幕，以显示SE后与A1启动子的相互作用增强。拟议的研究有望阐明如何调节A1表达以及在癫痫发生过程中如何改变该调节。这些研究的结果应促进开发新的疗法，以通过鉴定潜在的新的治疗靶标，这些疗法是针对Gabar亚基基因表达的潜在新治疗靶标。