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)基因表达及其改变的生理和病理后果 在ADH的表达中。我们假设ADH基因表达的差异会影响 酒精的代谢，酒精中毒的风险，以及酒精中毒的生理和病理后果 饮酒。为了开始检验这一假设，我们将确定控制ADH的区域 表达，识别这些区域的多态，然后分析这些多态是否会影响 基因表达。 我们将确定在人类ADH基因调控中重要的CW作用元件，与初级 重点研究I类基因和ADH7。它们有不同的表达模式，并产生 影响重要的代谢过程，包括乙醇和视黄醇的代谢。CW作用元素 将通过功能研究(转基因)和蛋白质结合分析相结合的方式进行鉴定 (DNasel足迹和凝胶延迟)。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，我们假设距离较远的侧翼序列是 在调节这组基因方面很重要。我们将通过研究更远距离的序列来检验这一假设， 从编码区延伸至少10kb。我们还将分析大染色体的调节 携带ADH基因组的片段(BAC)，以检测染色体环境中的潜在相互作用。 我们假设个体间调控序列的差异导致ADH基因的差异 表情。我们将识别和描述调控区域的多态，并测试它们的影响 关于基因在体外的表达。这两个目标将与CW-ACTING的本地化紧密结合 指导我们搜索多态的元素，以及我们对功能性多态的检测有助于 优先进一步研究CW-作用元素。 这些研究将有助于我们理解导致人与人之间差异的遗传因素。 个人在新陈代谢、药理和病理方面的饮酒影响。他们会 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.