Biased Agonism Mediated by the Glucocorticoid Receptor

糖皮质激素受体介导的偏向激动

• 批准号: RGPIN-2018-04312
• 负责人: Giembycz, Mark
• 金额: $ 2.33万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684184
• 关键词: Biased; Agonism; Mediated; Glucocorticoid; Receptor

Background****Glucocorticoids are a family of naturally-occurring and synthetic agonists, which regulate the expression of genes controlling a wide variety of physiological functions including metabolism, development, inflammation and the immune system. These genomic effects are mediated by the glucocorticoid receptor (GR), a ligand-activated transcription factor, which is a member of the nuclear hormone receptor (NHR) superfamily.******Current concepts of GR-mediated gene expression assume that GR adopts the same, static conformation when bound by an activating ligand (i.e. agonist). Accordingly, the magnitude of gene expression changes is governed by the transcriptional competency of the ligand-receptor complex, which is determined by the innate chemical structure of the agonist. However, structural biologists have unequivocally established that GR can adopt multiple, interchangeable conformations, which are differentially stabilized in an agonist-dependent manner. Borrowing from the literature on 7-transmembrane spanning receptors, this plasticity may allow GR to interact, preferentially, with one gene promoter (or population of promoters) over another leading to distinct, agonist-directed programs of gene expression by a process called biased agonism.*******Hypothesis****The overall hypothesis is that distinct programs of GR-mediated gene expression can be generated in a given cell type that depend on the innate structure of an activating ligand and its ability to create unique conformations of GR. This changes the complement and stoichiometry of obligatory co-factors that bind to GR and, thereby, its ability to interact productively at certain gene promoters over others.*******Aims**** To conduct a "proof-of-concept" study to establish GR-mediated gene expression bias;*** To validate, quantify and analyse, using bioinformatics approaches, gene expression bias;*** To explore in vitro the biological activity of biased GR agonists.******Anticipated Outcomes and Discovery Potential****This programme of research will apply biological, analytical and bioinformatics approaches, to establish a fundamental biological process of GR-mediated gene expression whereby distinct, transcriptional signatures are directed by the innate structure of an activating ligand. Many ligands have been identified with the potential to stabilise GR in distinct conformations and direct different patterns of gene expression through biased agonism. A ligand, by creating a unique, GR conformer, should be able to "program" a cell to preferentially express distinct populations of genes with attendant functional consequences. Establishing the principle of GR-mediated, biased agonism could be extrapolated to other NHRs, apply across species and be relevant to all biologists interested in the regulation of gene expression. ********

背景****糖皮质激素是一类天然存在和合成的激动剂，可调节基因的表达，从而控制多种生理功能，包括代谢、发育、炎症和免疫系统。这些基因组效应是由糖皮质激素受体 (GR) 介导的，糖皮质激素受体 (GR) 是一种配体激活的转录因子，是核激素受体 (NHR) 超家族的成员。****** GR 介导的基因表达的当前概念假设 GR 在与激活配体（即激动剂）结合时采用相同的静态构象。因此，基因表达变化的幅度由配体-受体复合物的转录能力控制，而配体-受体复合物的转录能力由激动剂的固有化学结构决定。然而，结构生物学家已经明确证实，GR 可以采用多种可互换的构象，这些构象以激动剂依赖性方式实现差异稳定。借用有关 7 次跨膜受体的文献，这种可塑性可能允许 GR 优先与一个基因启动子（或启动子群体）相互作用，而不是与另一个基因启动子相互作用，从而通过一种称为偏向激动的过程产生不同的、激动剂导向的基因表达程序。********假设****总体假设是，GR 介导的基因表达的不同程序可以在取决于先天结构的给定细胞类型中生成 激活配体的研究及其创建独特 GR 构象的能力。这改变了与 GR 结合的必需辅因子的补体和化学计量，从而改变了其在某些基因启动子上比其他基因启动子有效相互作用的能力。 ******目的**** 进行“概念验证”研究以建立 GR 介导的基因表达偏差；*** 使用生物信息学方法验证、量化和分析基因表达偏差；*** 探索体外 ******预期结果和发现潜力****该研究计划将应用生物学、分析学和生物信息学方法，建立 GR 介导的基因表达的基本生物学过程，其中独特的转录特征由激活配体的固有结构引导。许多配体已被鉴定具有将 GR 稳定在不同构象中的潜力，并通过偏向激动作用指导不同的基因表达模式。配体通过创建独特的 GR 构象异构体，应该能够“编程”细胞优先表达不同的基因群，并产生随之而来的功能后果。建立 GR 介导的偏向激动原理可以外推到其他 NHR，适用于跨物种，并与所有对基因表达调控感兴趣的生物学家相关。 ******