MOLECULAR STUDIES ON SEROTONERGIC GENE EXPRESSION

为了确定酒精中毒易感性的遗传贡献，我们重点关注 酒精能行为，因为酒精中毒的一种亚型与 降低血清素周转率5-羟色胺的生物合成受 色氨酸羟化酶（TPH），其是限速的。水平 色氨酸是血清素生物合成的前体， 色氨酸2，3-双加氧酶（TDO）。血清素能神经传递是 受5-HT 1A受体的突触前和突触后影响。我们 推测TPH、TDO和5-HT 1A遗传变异及其影响因素 控制它们的基因表达是酗酒的决定因素 脆弱性和相关行为。检测TDO基因表达， 第一次在大脑中。人类、小鼠和哺乳动物的多态性变体 猕猴TPH和人类和猕猴5-HT 1A受体等位基因， 通过SSCP分析鉴定。将人TPH基因定位于染色体上， 11p15.5。人类TPH基因多态性与脑脊液5-HIAA的相关性 酗酒冲动暴力的芬兰人TPH多态性 与酗酒暴力芬兰人的自杀行为有关。 多态 TPH和5 HT-1A等位基因正在测序中。因素和顺序 控制TPH和5-HT 1A表达的基因正在被鉴定。DNA 正在分析构造以描绘控制组织的区域- 特异性和调节性TPH表达。小鼠TPH启动子被 通过迁移率变动分析和DNA酶I足迹分析来分析， 鉴定调节TPH基因表达的转录因子， 它们的同源结合位点。

To identify genetic contributions to alcoholism vulnerability, we focus 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. Levels of tryptophan, a precursor in serotonin biosynthesis, are modulated by tryptophan 2,3-dioxygenase (TDO). Serotonergic neurotransmission is influenced pre- and postsynaptically by the 5-HT1A receptor. We hypothesize that genetic variants of TPH, TDO and 5-HT1A and factors controlling their gene expression are determinants of alcoholism vulnerability and related behaviors. TDO gene expression was detected for the first time in brain. Polymorphic variants of the human, mouse and macaque TPH and the human and macaque 5-HT1A receptor alleles were identified by SSCP analysis. The human TPH gene was mapped to chromosome 11p15.5. The human TPH polymorphism associated with CSF 5-HIAA concentration in alcoholic, impulsive, violent Finns. The TPH polymorphism associated with suicidal behavior in alcoholic violent Finns. Polymorphic TPH and 5HT-1A alleles are being sequenced. The factors and sequences controlling the expression of TPH and 5-HT1A are being identified. DNA constructions are being assayed to delineate regions controlling tissue- specific and regulated TPH expression. The mouse TPH promoter is being analyzed by mobility shift assay and DNase I footprint analysis to identify transcription factors which regulate TPH gene expression and their cognate binding sites.