Structure & Expression of Mammal ALC Dehydrogenase Genes

这项研究的长期目标是了解调节人类酒精的机制 脱氢酶（ADH）基因表达，以及改变的生理和病理后果 ADH表达。我们假设抗利尿激素基因表达的差异会影响 酒精代谢，酒精中毒的风险，以及酒精中毒的生理和病理后果 酒精消费。为了开始检验这一假设，我们将确定控制ADH的区域 表达，鉴定这些区域的多态性，然后分析这些多态性是否影响 基因表达。 我们将鉴定在人类ADH基因调控中重要的顺式作用元件， 重点关注I类基因和ADH 7。它们有不同的表达模式，并产生酶， 影响重要的代谢过程，包括乙醇和视黄醇的代谢。CW作用元件 将通过功能研究（转染）和蛋白质结合分析的结合来鉴定 （DNA酶1足迹和凝胶阻滞）。我们将鉴定与这些序列结合的转录因子。 ADH基因聚集在4号染色体上，我们假设远端侧翼序列是 对调节这组基因很重要。我们将通过研究更远的序列来验证这一假设， 从编码区延伸至少10kb。我们还将分析大染色体的调控， 在一些实施方案中，使用携带ADH基因组的BACs片段来检测染色体背景中的潜在相互作用。 我们推测ADH基因调控序列的个体间差异导致ADH基因的差异 表情我们将鉴定和描述调控区的多态性，并测试其作用 对体外基因表达的影响这两个目标将紧密结合， 指导我们寻找多态性的元素，以及我们对功能多态性的检测， 优先考虑进一步研究化学武器的作用因素。 这些研究将有助于我们了解在不同的遗传因素之间的差异 在酒精消费的代谢，药理学和病理学影响的个人。他们将 也增加了我们对基因调控的基本理解。

The long term goals of this research are to understand the mechanisms that regulate humanalcohol dehydrogenase (ADH) gene expression, and the physiological and pathological consequences of alterations in ADH expression. Wehypothesize that differences in the expression of the ADH genes affect the metabolism of alcohol, the risk for alcoholism, and thephysiological and pathological consequences of alcohol consumption. To begin testing this hypothesis we will identify the regions that control ADH expression, identify poly-morphisms in these regions, and then analyze whether these polymorphisms affect gene expression. We will identify cw-acting elements important in the regulation of the human ADH genes, with primary focus on the class I genes and ADH7. These have different patterns of expression, and produce enzymes that influence important metabolic processes including metabolism of ethanol and retinol. Cw-acting elements will be identified by a combination of functional studies (transfections) and protein-binding analyses (DNasel footprintingand gel retardation). We will identify transcription factors that bind to these sequences. The ADH genes are clustered on chromosome 4, and we hypothesize that distant flanking sequences are important in regulating this group of genes. We will test this hypothesis by studying more distant sequences, extending at least 10 kb from the coding regions. We will also analyze the regulation of large chromosomal segments (BACs) carrying groups of ADH genes to detect potential interactions in a chromosomal context. We hypothesize that inter-individual differences in regulatory sequences cause differences in ADH gene expression. We will identify and characterize polymorphisms in the regulatory regions and test their effects on gene expression in vitro. These two aims will be closely coupled, with the localization of cw-acting elements directing our search for polymorphisms, and our detection of functional polymorphisms helping to prioritize further study of the cw-acting elements. These studies will contribute to our understanding of the genetic factors underlyingdifferences among individuals in the metabolic, pharmacological and pathological effects of alcohol consumption. They will also increase our basic understanding of gene regulation.