GAD AND GABA-R CANDIDATE GENES FOR EPILEPSY

对人类患者的药理学研究和对动物的分析 模型表明，许多形式的癫痫涉及神经元功能障碍， 使用γ-氨基丁酸（GABA）作为主要成分的系统 神经传递素 本项目的目的是利用重组DNA 技术来分离编码两种蛋白质的基因， GABA能功能-谷氨酸脱羧酶（GAD）和GABA受体 （GABA-R）。 这些基因的结构改变可能是导致 癫痫病的症状有哪些？ 本项目将检验三个假设： 1.编码GAD或GABA-R多肽的基因是GAD或GABA-R多肽的遗传修饰位点。 青少年肌阵挛性癫痫（JME） 2. GAD或GABA-R基因之一的结构和表达是 在现有的癫痫遗传动物模型中， （听觉敏感的沙鼠，听源性癫痫敏感的小鼠， 蹒跚的老鼠）。 3.癫痫可以通过特异性阻断 GAD或GABA-R的基因。 为了验证这些假设，我们建议使用重组DNA 目前在实验室使用的技术。 我们建议分离出 GAD和GABA-R，并研究其结构和遗传， 实验动物和家庭与JME。 我们还将尝试 开发新的方法来研究候选基因在组织中的功能 培养细胞和转基因小鼠。

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.