Molecular Mechanisms of Glucocorticoid Hormone Action

描述(申请人提供)：了解监管机制 对于理解发育和基因表达是必不可少的 分化，因此，癌症和其他可能出现的疾病 流程出了问题。糖皮质激素和孕激素调节多种过程 在正常的生理和疾病中，包括怀孕、肺和乳房 发展、应激反应、炎症和癌症。它们的受体 类固醇激素通过调节靶基因转录来控制这些过程 基因。我们的长期目标是了解这些分子的细节 监管机制。这样的知识可以推动现有的 治疗方案和新的干预途径的发展， 尤其是内分泌依赖型肿瘤和炎症性疾病。这 应用程序解决了法规中两个非常广泛和基本的问题 关于基因表达的。第一个是染色质在基因表达和表达中的作用 第二个是两个几乎没有能力的转录因子是如何 区分单个DNA靶点可以调节非常不同的生物 行为。第一个目标的重点是应用我们已有的新战略 开发或带到实验室以维持糖皮质激素的循环 在体外转录系统中的受体活性。一把钥匙 该系统的特点是它使用染色质模板，以便 了解受体在更具生物学意义的情况下的作用机制 背景。第二个目标建立在第一个目标的基础上，即考察个人的角色 共调节蛋白在糖皮质激素受体中的体外作用。的作用 染色质的重塑和修饰将是一个特别的焦点。第三和 第四个目标是了解差异基因的机制。 糖皮质激素和孕激素受体的调节。我们将利用 我们最近在目标三中确定的差异表达基因 机械学研究。在目标四中，我们将扩展我们的小说发现 启动子周围的染色质环境可以通过以下方式影响基因调控 通过识别受体以定性和定量的方式 额外的例子和分析染色体的位置，以了解基础 这项规定。这些研究将共同做出重大贡献 有助于我们理解荷尔蒙的作用。

DESCRIPTION (provided by applicant): Understanding the mechanisms of regulation of gene expression is essential to a comprehension of development and differentiation, and thus, cancer and other disorders that may arise when these processes go awry. 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 regulation transcription of target genes. Our long term goal is to understand the molecular details of 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. This application addresses two very broad and fundamental issues in the regulation of gene expression. The first is the role of chromatin in gene expression and the second is how two transcription factors that have little ability to distinguish individual DNA target sites can mediate very different biological actions. The focus of the first aim is to apply new strategies we have developed or brought to the lab to maintain the recycling of glucocorticoid receptor activity in the context of an in vitro transcription system. A key feature of this system is that it employs chromatin templates in order to understand mechanisms of receptor action in a more biologically relevant context. The second aim builds on the first to examine the role of individual coregulatory proteins in glucocorticoid receptor action in vitro. The role of chromatin remodeling and modification will be a special focus. The third and fourth aims are directed toward understanding mechanisms of differential gene regulation by glucocorticoid and progesterone receptors. We will exploit differentially expressed genes we have recently identified in aim three for mechanistic studies. In aim four we will expand on our novel finding that the chromatin environment surrounding a promoter can influence gene regulation by receptors in both a qualitative and quantitative fashion by identifying additional examples and analyzing the chromosomal sites to understand the basis of this regulation. Together these studies will make significant contributions to our understanding of hormone action.