MOLECULAR STUDIES ON TRYPTOPHAN HYDROXYLASE GENE EXPRESSION

为了确定酒精中毒的遗传决定因素，我们重点研究了 与5-羟色胺功能相关的人类和小鼠行为。 5-羟色胺的合成受色氨酸酶的活性控制 羟基酶(TRH)。TRH是一种限速酶，在 这种神经递质。因此，我们假设TRH的控制 TRH的基因表达和遗传变异在发病中起重要作用。 5-羟色胺相关行为的病因学。我们已经克隆并测序 小鼠促肾上腺皮质激素释放激素(TRH)基因及其编码区TRH基因定位于 染色体7。该基因的克隆和测序也使 其假定的监管区域的特征以及其 内含子/外显子边界。我们正在扩展这些研究，以调查 控制该基因表达的因素和DNA序列。等位基因 通过SSCP分析，TRH基因的变异体在这两种疾病中都被鉴定出来 人类和老鼠。利用CEPH家族，我们正在绘制 人类基因组中的色氨酸羟基酶基因。我们正在研究 冲动性和冲动性行为与该基因多态性的关系 酗酒的芬兰人。在重组LSXSS近交系小鼠中，酒精 诱导睡眠时间与TRH DNA显著相关 多态。正在生产的DNA结构将被插入 进入老鼠的基因组。这些研究和关于自然遗传的研究 TRH的变种将被用来定量5-羟色胺能成分 以及确定组织所需的DNA序列 特定的基因表达。

In order to identify genetic determinants of alcoholism we have focused on human and murine behaviors that are associated with serotonin function. Serotonin synthesis is controlled by the activity of the enzyme tryptophan hydroxylase (TrH). TrH is the rate-limiting enzyme in the production of this neurotransmitter. Therefore, we hypothesize that control of the TrH gene expression and genetic variants of TrH play a major role in the etiology of serotonin-associated behaviors. We have cloned and sequenced the cDNA and gene coding for murine TrH. The TrH gene was located to chromosome 7. Cloning and sequencing of this gene also allowed the characterization of its putative regulatory region as well as its intron/exon boundaries. We are extending these studies to investigate the factors and DNA sequences controlling the expression of this gene. Allelic variants of the TrH gene have been identified by SSCP analysis in both humans and mice. Utilizing the CEPH families, we are mapping the tryptophan hydroxylase gene in the human genome. We are studying the relationship of this polymorphism to impulsive behavior in impulsive and alcoholic Finns. In recombinant LSXSS inbred strains of mice, alcohol induced sleep time showed a significant association with the TrH DNA polymorphism. DNA constructions are being produced that will be inserted into the genome of mice. These studies and those on natural genetic variants of TrH will be used to quantitate the serotonergic component of behavior as well as to determine the DNA sequences required for tissue specific gene expression.