GAD AND GABA-R CANDIDATE GENES FOR EPILEPSY

GAD 和 GABA-R 癫痫候选基因

• 批准号: 3404458
• 负责人: ALLAN J TOBIN
• 金额: $ 15.07万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 1988-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3404458
• 关键词: biological models; epilepsy; erythrocytes; gamma aminobutyrate; gene expression; genetic library; genetic mapping; genetic models; messenger RNA; molecular cloning; neurotransmitters; nucleic acid sequence; thalassemia; tissue /cell culture

Both pharmacological studies on human patients and the analysis of animal models indicate that many forms of epilepsy involve dysfunction of neuron systems that use gamma-aminobutyric acid (GABA) as a principal neurotransmitter. The purpose of this project is to use recombinant DNA techniques to isolate the genes coding for two proteins that are central to GABA-ergic functions -- glutamic acid decarboxylase (GAD) and GABA receptor (GABA-R). Altered structures of these genes may be responsible for the inheritance of some forms of epilepsy. This project will test three hypotheses: 1. A gene coding for a GAD or GABA-R polypeptide is the site of the genetic lesion in Juvenile Myoclonic Epilepsy (JME). 2. The structure and expression of one of the GAD or GABA-R genes is altered in the existing genetic animal models of epilepsy (seizure-sensitive gerbils, audiogenic seizure sensitive mice, and tottering mice). 3. Epilepsy can be produced in mice by specifically blocking the expression of the genes for GAD or GABA-R. In order to test these hypotheses, we propose to employ recombinant DNA techniques now in use in this laboratory. We propose to isolate the genes for GAD and GABA-R and to study their structure and inheritance both in experimental animals and in families with JME. We will also attempt to develop new methods to study the functions of the candidate genes in tissue culture cells and in transgenic mice.

对人类患者的药理研究和对动物的分析 模型表明，许多形式的癫痫与神经元功能障碍有关。 以γ-氨基丁酸(GABA)为主要成分的体系 神经递质。这个项目的目的是使用重组DNA 分离编码两种蛋白质的基因的技术 GABA能神经功能--谷氨酸脱羧酶和GABA受体 (GABA-R)。这些基因结构的改变可能是导致 遗传某些形式的癫痫。 该项目将检验三个假设： 1.编码GAD或GABA-R多肽的基因是 青少年肌阵挛癫痫(JME)的皮损。 2.GAD或GABA-R基因之一的结构和表达 现有癫痫遗传动物模型的改变 (癫痫敏感型沙土鼠、听源性癫痫敏感型小鼠和 摇摇欲坠的老鼠)。 3.通过特异性地阻断该基因的表达，可以在小鼠中产生癫痫 GAD或GABA-R的基因。 为了验证这些假设，我们建议使用重组DNA 这个实验室目前正在使用的技术。我们建议分离这些基因 GAD和GABA-R并研究它们的结构和遗传 实验动物和患有JME的家庭。我们还将尝试 开发新方法研究候选基因在组织中的功能 培养细胞和转基因小鼠。