REGULATION OF HEPATOCELLULAR FUNCTION BY GROWTH HORMONE

描述：该提案涉及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 抑制子）2位点。 将检验三个假设。 首先是 Stat2.1基因的调节是通过Stat 5在一个特定的细胞中的结合来介导的。 GHRE内的两个站点的合作方式。 第二是 另外的蛋白质与Stat 5相互作用以介导调节。 三是 通过Stat 5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， Stat 5-蛋白质相互作用 提出了三个具体目标来测试这些 假设 1. 研究人员将进一步确定核蛋白 在Spi 2.1模型中对GH作用至关重要，证明Stat 5 是Spi 2.1基因激活所必需的，研究YY 1在GH 作用，确定糖皮质激素受体的作用，并评估 Stat 5的丝氨酸磷酸化的作用。 2. 调查员会检查 GHRE的功能架构，探讨 在对GH的反应中成对的GAS样元件，区分 与Spi 2.1 GHRE结构相关的DNA元件的特征， 不响应GH，并定义Spi 2.1启动子中的其他元件 对GH的反应很重要。 3. 研究人员将比较 GH和IL-6在Spi 2.1基因表达中的作用，定义了IL-6 反应元件和核因子结合Spi 2.1， IL-6与GH反应的比较，从而进一步了解 Spi 2.1对GH反应的特异性。

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.