Hormonal Regulation of Ethanol Metabolism

乙醇代谢的激素调节

• 批准号: 8119297
• 负责人: ESTEBAN MEZEY
• 金额: $ 5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119297
• 关键词: Acetaldehyde; Affect; Affinity; Alcohol Dehydrogenase I; Alcohol dehydrogenase; Alcoholic Liver Diseases; Binding; Collagen; Collagen Gene; Elements; Ethanol; Ethanol Metabolism; Fibrosis; Gene Expression; Genes; Genetic Transcription; Hepatocyte; Hormones; Human; Individual; Investigation; Lead; Leptin; Lipopolysaccharides; Mediating; Mediator of activation protein; Modification; Nitric Oxide; Pathogenesis; Rattus; Regulation; Role; Signal Transduction; Signal Transduction Pathway; Trans-Activators; Transact; Transforming Growth Factor alpha; Transforming Growth Factor beta; alpha1 Type 1 Collagen; cytokine; fibrogenesis; hormone regulation; in vivo; oxidant stress; oxidation; promoter

DESCRIPTION (provided by applicant): The objectives of the proposed studies are two-fold: 1) To investigate the mechanisms of the effects of cytokines and hormones on the regulation of rat class I alcohol dehydrogenase (ADH). These studies include characterization of trans-acting factors that regulate expression of the gene, and determination of mechanisms whereby cytokines and hormones affect transcription. 2) To study the mechanisms whereby acetaldehyde, the product of ethanol oxidation by ADH, stimulates fibrogenesis. These studies are focused on identifying trans-acting factors that regulate expression of the type I collagen genes, and determining whether the effect of acetaldehyde is mediated by modification of the amounts or binding affinity of these trans-acting factors to the collagen genes. The two objectives are related in that changes in ADH and ethanol oxidation lead to acetaldehyde formation which is an important factor in the pathogenesis of alcoholic liver disease and fibrosis. Lipopolysaccharide (LPS) administration in vivo increased ADH. Since LPS stimulates release of cytokines, it will now be determined whether the effect of LPS on ADH is mediated by cytokines. Furthermore, the effects of cytokines on ADH will be determined in hepatocyte culture, and the signaling and transcription mechanisms whereby cytokines may affect ADH will be investigated. Transforming growth factor beta (TGFbeta) is a principal stimulator of fibrogenesis. The plan is to identify the trans-acting factor or factors that mediate the effect of TGFbeta in stimulating the human alpha1 (I) collagen promoter, the identity and role of the TGFbeta binding elements and the trans-acting factor or factors binding the promoter in mediating the activating effect of acetaldehyde on the promoter. Furthermore, the role of oxidant stress and nitric oxide as mediators of the activating effect of TGFalpha and acetaldehyde on the human alpha1 (I) collagen promoter will be investigated.

描述（由申请人提供）：拟议研究的目的有两个：1）研究细胞因子和激素对大鼠I类乙醇脱氢酶（ADH）调节的影响机制。这些研究包括调节基因表达的反式作用因子的表征，以及细胞因子和激素影响转录的机制的确定。 2) 研究ADH氧化乙醇的产物乙醛刺激纤维发生的机制。这些研究的重点是鉴定调节 I 型胶原蛋白基因表达的反式作用因子，并确定乙醛的作用是否是通过改变这些反式作用因子与胶原蛋白基因的量或结合亲和力来介导的。这两个目标是相关的，ADH 和乙醇氧化的变化导致乙醛形成，乙醛是酒精性肝病和纤维化发病机制的重要因素。体内脂多糖 (LPS) 增加 ADH。由于LPS刺激细胞因子的释放，现在将确定LPS对ADH的作用是否是由细胞因子介导的。此外，将在肝细胞培养物中确定细胞因子对 ADH 的影响，并研究细胞因子可能影响 ADH 的信号传导和转录机制。转化生长因子β (TGFbeta) 是纤维发生的主要刺激剂。该计划旨在鉴定介导 TGFbeta 在刺激人 α1 (I) 胶原蛋白启动子中的作用的反式作用因子，TGFbeta 结合元件和结合启动子的反式作用因子的身份和作用。介导乙醛对启动子的激活作用。此外，还将研究氧化应激和一氧化氮作为 TGFα 和乙醛对人 α1 (I) 胶原蛋白启动子的激活作用的介质的作用。