REGULATION OF HEPATOCELLULAR FUNCTION BY GROWTH HORMONE

生长激素对肝细胞功能的调节

• 批准号: 6150625
• 负责人: Susan A. Berry
• 金额: $ 23.36万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150625
• 关键词: affinity chromatography; biological signal transduction; corticosteroid receptors; gene expression; gene induction /repression; genetic promoter element; genetic regulatory element; hormone regulation /control mechanism; immunoprecipitation; interleukin 6; laboratory rat; liver cells; protease inhibitor; serine proteinases; somatotropin; tissue /cell culture; transcription factor; transfection

DESCRIPTION: This proposal addresses the molecular basis of growth hormone action in the liver through examination of the rat Spi I (serine protease inhibitor) 2 locus. Three hypotheses will be tested. The first is that regulation of the Stat 2.1 gene is mediated by binding of Stat5 in a cooperative fashion to two sites within the GHRE. The second is that additional proteins interact with Stat5 to mediate regulation. The third is that specificity of GH regulation through the Stat5 pathway is achieved through the unique architecture of the GHRE in the Spi 2.1 gene and these Stat5-protein interactions. Three specific aims are proposed to test these hypotheses. 1. The investigator will further define the nuclear proteins critical for GH action in the Spi 2.1 model, establishing proof that Stat5 is necessary for Spi 2.1 gene activation, examining the role of YY1 in GH action, determining the role of glucocorticoid receptor, and evaluating the role of serine phosphorylation of Stat5. 2. The investigator will examine the functional architecture of the GHRE, exploring the significance of paired GAS-like elements in the response to GH, distinguishing characteristics of DNA elements structurally related to the Spi 2.1 GHRE but not responsive to GH, and defining other elements in the Spi 2.1 promoter important in the response to GH. 3. The investigator will compare the actions of GH and IL-6 in Spi 2.1 gene expression, defining the IL-6 response element and the nuclear factors binding to Spi 2.1 in response to IL-6 with comparison to the GH response, thereby furthering understanding of the specificity of the Spi 2.1 response to GH.

描述：该提案阐述了生长激素的分子基础 通过检查大鼠 Spi I（丝氨酸蛋白酶）在肝脏中的作用 抑制剂）2个位点。 将测试三个假设。 第一个是 Stat 2.1 基因的调节是通过 Stat5 的结合介导的 GHRE 内的两个站点的合作方式。 第二个是 其他蛋白质与 Stat5 相互作用以介导调节。 第三个是 通过 Stat5 途径实现 GH 调节的特异性 通过 Spi 2.1 基因中 GHRE 的独特结构以及这些 Stat5-蛋白质相互作用。 提出了三个具体目标来测试这些 假设。 1. 研究者将进一步定义核蛋白 对 Spi 2.1 模型中的 GH 作用至关重要，证明 Stat5 对于 Spi 2.1 基因激活是必需的，检查 YY1 在 GH 中的作用 作用，确定糖皮质激素受体的作用，并评估 Stat5 丝氨酸磷酸化的作用。 2. 调查员将检查 GHRE 的功能架构，探讨 GH 响应中配对的 GAS 样元件，区分 结构上与 Spi 2.1 GHRE 相关的 DNA 元件的特征，但是 对 GH 不敏感，并在 Spi 2.1 启动子中定义其他元件 对 GH 的反应很重要。 3. 研究者将比较 GH 和 IL-6 在 Spi 2.1 基因表达中的作用，定义 IL-6 响应元件和核因子与 Spi 2.1 结合响应 IL-6 与 GH 反应进行比较，从而进一步了解 Spi 2.1 对 GH 反应的特异性。