MOLECULAR PATHOPHYSIOLOGY OF ALCHOLIC LIVER DISEASE

酒精性肝病的分子病理生理学

• 批准号: 3462679
• 负责人: FRANCIS R WEINER
• 金额: $ 12.42万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1990-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3462679
• 关键词: Cercopithecidae; DNA methylation; alcoholic liver cirrhosis; alcoholism /alcohol abuse; alleles; biological polymorphism; biopsy; collagen; corticosteroids; fibrogenesis; fibronectins; genetic library; genetic markers; genetic promoter element; genetic transcription; histopathology; human subject; laboratory rat; liver cells; messenger RNA; molecular cloning; molecular pathology; nucleic acid hybridization; nucleic acid sequence; procollagen; protein biosynthesis; sex hormones; tissue /cell culture

The objectives are to obtain a better understanding of the molecular effects of alcohol upon hepatic function as well as the pathogenesis of hepatic fibrosis in alcoholic liver disease. Two general areas of inquiry will be investigated: (1) What levels of gene regulation and specifically collagen gene regulation are affected in alcoholic liver disease? This will involve an analysis of mRNA steady state levels by cell free protein synthesis and RNA-DNA hybridization. Quantitative determinations of changes in several specific mRNA species including types I, III, and IV procollagen, albumin, fibronectin and -actin will be undertaken. Nuclear transcriptional run-off analysis will be performed in order to examine the basis for observed changes in steady state mRNA contents. Collagen gene promoter structure and function will be determined by constructing partial genomic libraries from cirrhotics and non-cirrhotic alcoholics, isolating and purifying the collagen promoter, and analyzing it by means of S1 nuclease sensitivity methylation, DNA sequencing, and use of a transient expression vector (pSV-0-CAT). These latter studies may explain variations in an individual's fibrotic response to alcohol. (2) What factors predispose an individual to develop alcoholic cirrhosis? This will involve a genetic analysis of the collagen gene using DNA polymorphisms and analysis of the role of sex hormones and corticosteroids in hepatic collagen synthesis using cell culture techniques, molecular hybridization studies and in vivo transient expression vector analysis. The results of such experiments will help us expand our knowledge of the molecular mechanisms responsible for hepatic fibrosis in man. This knowledge will help in developing diagnostic methods for evaluating fibrogenesis predicting susceptibility to develop cirrhosis, and provide the basis for better therapy. These studies will also facilitate my long term objective to become an independent investigator in academic hepatology with expertise in current areas of molecular biology.

目的是为了更好地理解分子

项目成果

Regulation of gene expression by insulin and tumor necrosis factor alpha in 3T3-L1 cells. Modulation of the transcription of genes encoding acyl-CoA synthetase and stearoyl-CoA desaturase-1.

3T3-L1 细胞中胰岛素和肿瘤坏死因子 α 对基因表达的调节。

• 发表时间: 1991
• 期刊: The Journal of biological chemistry
• 作者: Weiner,FR;Smith,PJ;Wertheimer,S;Rubin,CS
• 通讯作者: Rubin,CS