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 与血清素功能相关的人类和鼠类行为。 血清素的合成是由色氨酸酶的活性控制的 羟化酶（TrH）。 TrH是生产中的限速酶， 这种神经递质 因此，我们假设控制TrH TrH的基因表达和遗传变异在这一过程中起主要作用。 曲阜宁相关行为的病因学。 我们克隆并测序了 编码鼠TrH的cDNA和基因。 TrH基因被定位于 7号染色体。 该基因的克隆和测序也使得 表征其推定的调控区以及其 内含子/外显子边界。 我们正在扩展这些研究， 控制该基因表达的因子和DNA序列。 等位基因 TrH基因的变体已经通过SSCP分析在两种细胞中鉴定出来， 人类和老鼠 利用CEPH家族，我们正在绘制 色氨酸羟化酶基因。 我们正在研究 这种多态性与冲动行为的关系， 芬兰酒鬼 在重组LSXSS近交系小鼠中， 诱导睡眠时间与TrH DNA显著相关 多态 DNA结构正在产生， 植入到老鼠的基因组中。 这些研究和那些关于自然遗传的研究 TrH的变体将用于定量 行为以及确定组织所需的DNA序列 特异性基因表达

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.