MOLECULAR STUDIES ON SEROTONERGIC GENE EXPRESSION

为了确定遗传对酒精中毒易感性的贡献，我们将重点放在 对酒精能行为的影响，因为酒精中毒的一种亚型与 血清素周转率下降 5-羟色胺的生物合成受 色氨酸羟化酶（TPH），这是限速的。 我们假设 TPH和TDO的遗传变异以及控制它们基因的因素 表达在行为中起着重要作用。 我们克隆并测序了 小鼠TPH基因的cDNA和基因。 将人TPH基因定位于染色体11p15.5。 人类TPH 多态性与酒精中毒患者脑脊液5-HIAA浓度相关， 冲动的芬兰暴力罪犯 多态性与 有自杀企图和多次自杀企图史， 酗酒暴力的芬兰人 多态性TPH等位基因正在被 测序 控制基因表达的因子和DNA序列 小鼠TPH基因正在被鉴定。 DNA区域控制 组织特异性和组成型表达已经被鉴定， DNA融合构建体。 这些地区正在分析， 电泳迁移率变动分析以鉴定转录因子 以及它们调节TPH基因表达的同源结合位点。 RBP- 发现Jk负调控TPH基因表达。 我们已经克隆 RBP-Jk，它正在被表征。

To identify genetic contributions to alcoholism vulnerability, we focused on serotonergic behaviors, since a subtype of alcoholism is associated with decreased serotonin turnover. Serotonin biosynthesis is governed by tryptophan hydroxylase (TPH), which is rate-limiting. We hypothesize that genetic variants of TPH and TDO and factors controlling their gene expression play a major role in behavior. We cloned and sequenced the cDNA and gene for murine TPH gene. The human TPH gene was mapped to chromosome 11p15.5. The human TPH polymorphism associated with CSF 5-HIAA concentration in alcoholic, impulsive, Finnish violent offenders. The polymorphism associated with history of suicidal attempts and of multiple suicidal attempts in alcoholic, violent Finns. The polymorphic TPH alleles are being sequenced. The factors and DNA sequences controlling the expression of the mouse TPH gene are being identified. DNA regions controlling tissue-specific and constitutive expression have been identified using DNA fusion constructs. These regions are being analyzed by electrophoretic mobility shift analysis to identify transcription factors and their cognate binding sites that regulate TPH gene expression. RBP- Jk was found to negatively regulate TPH gene expression. We have cloned the RBP-Jk and it is being characterized.