Molecular Mechanisms of Glucocorticoid Hormone Action

糖皮质激素作用的分子机制

• 批准号: 6471953
• 负责人: STEVEN K NORDEEN
• 金额: $ 28.51万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6471953
• 关键词: Baculoviridae; DNA; DNA footprinting; acetylation; cell free system; chromatin; corticosteroid receptors; fluorescent dye /probe; gene expression; genetic regulation; genetic regulatory element; glucocorticoids; histones; hormone regulation /control mechanism; immunoprecipitation; intermolecular interaction; method development; mouse mammary tumor virus; nucleic acid structure; nucleosomes; progesterone receptors; protein structure function; reporter genes; site directed mutagenesis; tissue /cell culture; transcription factor

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.

描述（由申请人提供）：了解监管机制 基因表达是理解发育和 分化，因此，癌症和其他疾病，可能会出现时，这些 流程就会出错糖皮质激素和孕激素调节许多过程 在正常生理和疾病中，包括怀孕、肺和乳房 发育、应激反应、炎症和癌症。这些受体 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。这些知识可以推动现有的 治疗方案和开发新的干预途径， 特别是在内分泌依赖性瘤形成和炎性疾病中。这 申请解决了法规中两个非常广泛和基本的问题 的基因表达。首先是染色质在基因表达中的作用， 第二个是两个转录因子， 区分单个DNA靶位点可以介导非常不同的生物学效应。 行动第一个目标的重点是应用我们拥有的新战略， 开发或带到实验室来维持糖皮质激素的循环 在体外转录系统的情况下的受体活性。一个关键 该系统的特征在于它采用染色质模板， 了解受体的作用机制，在一个更生物相关的 上下文第二个目标建立在第一个目标的基础上， 体外糖皮质激素受体作用中的共调节蛋白。的作用 染色质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， 通过糖皮质激素和孕酮受体调节。我们将利用 我们最近在目标三中发现了差异表达的基因， 机械研究。在目标四中，我们将扩展我们的新发现， 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： 通过鉴定，以定性和定量的方式检测受体 额外的例子和分析染色体位点，以了解基础 这一规定。这些研究将共同作出重大贡献 我们对激素作用的理解。