MOLECULAR MECHANISMS OF GLUCOCORTICOID HORMONE ACTION

糖皮质激素和孕激素调节正常的多种过程 生理和疾病，包括怀孕、肺和乳房发育， 压力反应、炎症和癌症。它们的受体 类固醇激素通过调节转录调控这些过程。 靶基因。我们的长期目标是了解这些监管规定 机械装置。这样的知识可以推动现有的 治疗方案和开发新的治疗途径 干预，特别是对内分泌依赖性肿瘤和 炎症性疾病。第一个目标的重点是 类固醇反应机制与其他信号转导途径。 激活对特异性细胞信号转导的抑制 途径可以显著影响类固醇受体介导的 转录调控。荷尔蒙反应可能会增强，或者 抑制率高达10倍。我们建议确定塔塔的区域 结合蛋白是蛋白之间偶联的靶蛋白 激酶A途径与糖皮质激素依赖的转录和TO 确定这种耦合的中介者。在某些情况下，类固醇 受体甚至可能在没有激素的情况下被激活。其他内容 实验将调查差动能力的基础 糖皮质激素和孕激素受体将经历激素非依赖性 激活。我们将测试假设，这是一个功能性的 糖皮质激素和糖皮质激素的不同定位的后果 黄体酮受体。在第二个目标中，我们将重点放在 控制基因表达差异控制的机制 糖皮质激素和孕激素受体。因为有几种类固醇 受体具有相似的，如果不是相同的，DNA序列识别 特性，即靶基因的差异调控如何 是理解荷尔蒙生物学的核心 行动。提出了一种综合的方法来确定新的例子 差分归纳法，并研究支配 目标推动者的不同反应。对这些来说至关重要 研究是使用基于逆转录病毒的陷阱系统来识别 差异调控的启动子和染色体位置。

Glucocorticoids and progestins regulate numerous processes in normal physiology and disease including pregnancy, lung and breast development, stress response, inflammation, and cancer. The receptors for these steroid hormones control these processes by regulating transcription of target genes. Our long term goal is to understand these regulatory mechanisms. Such knowledge could drive the improvement of existing therapeutic regimens and the development of novel avenues for intervention, particularly in endocrine-dependent neoplasia and inflammatory disease. The focus of the first aim is the coupling of steroid response mechanisms with other signal transduction pathways. The activation of inhibition of specific cellular signal transduction pathways can dramatically influence steroid receptor-mediated transcriptional regulation. The hormone response may be potentiated or inhibited up to 10-fold. We propose to identify the region of the TATA biding protein that is the target for the coupling between the protein kinase A pathway and glucocorticoid-dependent transcription and to identify the mediators of this coupling. In some circumstances, steroid receptors may even be activated in the absence of hormone. Additional experiments will investigate the basis of the differential capacity of glucocorticoid and progesterone receptors to undergo hormone-independent activation. We will test the hypothesis that this is a functional consequence of differential localization of the glucocorticoid and progesterone receptors. In the second aim we will focus on the mechanisms that govern differential control of gene expression by glucocorticoid and progesterone receptors. Since several steroid receptors have similar, if not identical, DNA sequence recognition properties, the question of how differential regulation of target genes is accomplished is central to understanding the biology of hormone action. A comprehensive approach is proposed to identify new examples of differential induction and to investigate the mechanisms that govern differential responsiveness of target promoters. Central to these studies is the use of a retrovirus-based trap system to identify differentially regulated promoters and chromosomal locations.