REGULATION OF HEPATOCELLULAR FUNCTION BY GROWTH HORMONE

描述：该提案涉及生长激素的分子基础。 大鼠SPI I(丝氨酸蛋白酶)在肝脏中的作用 抑制物)2个基因座。三个假说将被检验。第一个是 Stat 2.1基因的调节是由Stat5结合介导的。 在GHRE内的两个地点的合作方式。第二个就是 更多的蛋白质与Stat5相互作用，介导调节。第三个是 通过Stat5途径实现GH调节的特异性 通过SPI2.1基因中GHRE的独特结构和这些 STAT5-蛋白质相互作用。提出了三个具体的目标来测试这些 假设。1.调查员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 是SPI2.1基因激活所必需的，检测YY1在生长激素中的作用 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.调查员将审查 GHRE的功能架构，探讨了 成对的类气体元素对生长激素的响应，区分 结构上与SPI 2.1 GHRE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 在对生长激素的反应中很重要。3.调查员将比较 GH和IL-6在定义IL-6的SPI2.1基因表达中的作用 响应元件和结合SPI 2.1的核因子对 IL-6与生长激素反应的比较，从而加深对 SPI2.1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.