MOLECULAR STUDIES ON TRYPTOPHAN HYDROXYLASE GENE EXPRESSION

家庭和双胞胎研究表明， 酒精中毒的发展。 为了确定这些问题，我们重点关注 酒精能行为，因为酒精中毒与减少 血清素周转率 在中缝神经元中， 控制色氨酸羟化酶（TPH）的酶活性。 由于TPH是 5-羟色胺合成的限速酶，我们假设变异 TPH和控制TPH基因表达的因素，在 过敏性行为。 我们克隆并测序了该cDNA和编码 对于鼠TPH。 这使得假定的规则的特征 区域以及其内含子/外显子结构。 小鼠TPH基因是 将人TPH基因定位于染色体区域 11p15.5。 人类、小鼠和猕猴TPH等位基因的多态性变体 通过SSCP分析鉴定。 人类TPH多态性与 CSF 5-HIAA和血糖浓度以及自杀倾向 冲动型酗酒者的行为 小鼠TPH多态性占 重组近交系中酒精诱导的睡眠时间差异为6% LS X SS小鼠。 猕猴中的TPH基因型正在调查中。 这些多态性等位基因正在测试其对TPH基因的影响 表情各种药物正在测试它们对TPH基因的影响 表情 DNA构建完成后， 组织特异性和药物激活和抑制的TPH基因表达。 DNA酶I足迹转录因子结合的研究正在进行中 通过了解自然遗传学， 变异以及确定DNA序列和所需的因素， TPH基因表达。

Family and twin studies have implicated a genetic contribution to the development of alcoholism. To identify these, we have focused on serotonergic behaviors, since alcoholism is associated with decreased serotonin turnover. The synthesis of serotonin, in raphe neurons, is governed tryptophan hydroxylase (TPH) enzyme activity. Since TPH is the rate-limiting enzyme in serotonin synthesis, we hypothesize that variants of TPH and factors controlling TPH gene expression, play a major role in serotonergic behaviors. We cloned and sequenced the cDNA and gene coding for murine TPH. This allowed the characterization of putative regualtory regions as well as its intron/exon structure. The murine TPH gene was mapped to chromosome & and the human TPH gene to chromosomal region 11p15.5. Polymorphic variants of the human, mouse and macaque TPH alleles were identified by SSCP analysis. The human TPH polymorphism associated with CSF 5-HIAA and blood glucose concentrations as well as suicidal behavior in implusive alcoholics. The mouse TPH polymorphism accounted for 6% of the variance in alcohol induced sleep time in recombinant inbred LS X SS mice. The TPH genotypes in the macaques are under investigation. These polymorphic alleles are being tested for their effect on TPH gene expression. Various drugs are being tested for their effect on TPH gene expression. DNA constructions were made, that are being assayed in tissue-specific and drug-activated and repressed TPH gene expression. Studies are under way to DNase I footprint transcription factor binding sites in the serotonergic behaviors by understanding natural genetic variants as well as determining the DNA sequences and factors required for TPH gene expression.