REGULATION OF LIVER GENE EXPRESSION

肝脏基因表达的调节

• 批准号: 6107600
• 负责人: MARIO CHOJKIER
• 金额: $ 5.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107600
• 关键词: DNA binding protein; carbon tetrachloride; collagen; disease /disorder model; fibroblasts; fibrogenesis; fibrosis; gene expression; genetic regulatory element; genetic transcription; genetically modified animals; in situ hybridization; iron storage disorder; laboratory mouse; laboratory rat; liver cells; liver disorder; liver metabolism; messenger RNA; peroxidation; transcription factor; transfection

Although collagen overproduction is a critical step in the development of liver cirrhosis, the regulation of collagen gene expression, and its cell(s) of origin remain unclear. Lipid peroxidation is associated with the tissue injury and fibrogenesis of several hepatic disorders, including iron-overload, porphyria, and ethanol, and CC1-4-induced toxicity. We have recently shown that products of lipid peroxidation, such as reactive aldehydes, stimulate collagen gene expression in vitro (23), and we suggested that this could be the mechanism by which hepatic injuries are sometimes followed by fibrogenesis. To gain insight into the mechanisms underlying hepatic fibrosis, we will study the in vivo expression of collagen genes in hepatocytes and nonparenchymal cells in two animal models of lipid peroxidation and fibrogenesis: CC1-4-induced hepatic injury and chronic iron overload. Also we will assess the relationship between lipid peroxidation and collagen gene expression in cultured cells and in these animal models of hepatic fibrosis. Additional experiments will define the regulatory elements of the collagen alpha1(I) gene in cultured cells and in transgenic mice under control conditions and conditions of enhanced lipid peroxidation. The specific aims of this proposal are to assess: 1) The cellular origin of hepatic collagen gene expression. 2) The regulation of collagen gene expression by lipid peroxidation in cultured fibroblasts. 3) The regulation of collagen gene expression by lipid peroxidation in primary rat hepatocyte and hepatic lipocyte cultures. The long range goal is to identify the factors responsible for fibrogenesis in hepatic lipid peroxidation and then test therapeutic interventions.

虽然胶原蛋白的过度生产是发展的关键步骤， 肝硬化，胶原基因表达调控， 细胞的来源仍不清楚。脂质过氧化作用与 几种肝脏疾病的组织损伤和纤维化，包括 铁超负荷、卟啉症和乙醇以及CCl-4诱导的毒性。我们有 最近表明，脂质过氧化产物，如反应性 醛类，刺激胶原蛋白基因的体外表达（23），我们 这可能是肝损伤的机制， 有时还伴有纤维化。 为了深入了解肝纤维化的潜在机制，我们将 研究肝细胞中胶原基因的体内表达， 非实质细胞在两种动物模型的脂质过氧化和 纤维化：CCl-4诱导的肝损伤和慢性铁超负荷。也 我们将评估脂质过氧化和胶原蛋白之间的关系， 在培养的细胞和这些肝移植动物模型中的基因表达 纤维化另外的实验将定义以下的调控元件： 培养细胞和转基因小鼠中的胶原蛋白α 1（I）基因在 控制条件和增强脂质过氧化的条件。 这项建议的具体目的是评估： 1)肝胶原基因表达的细胞起源。 2)脂质过氧化对肝细胞胶原基因表达的调控 培养成纤维细胞。 3)脂质过氧化对肝细胞胶原基因表达的调控 原代大鼠肝细胞和肝脂肪细胞培养物。 长期目标是确定导致 肝脂质过氧化纤维化，然后测试治疗 干预措施。