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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=712916
• 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 糖皮质激素是一类自然产生的和合成的激动剂，调节控制包括新陈代谢、发育、炎症和免疫系统在内的各种生理功能的基因的表达。这些基因组效应是由糖皮质激素受体(GR)介导的，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。 目前关于GR介导的基因表达的概念假设，当GR被激活的配体(即激动剂)结合时，GR采用相同的静态构象。因此，基因表达变化的大小取决于配体-受体复合体的转录能力，而转录能力又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地证实，GR可以采用多种可互换的构象，这些构象以激动剂依赖的方式差异稳定。借用7-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(或一组启动子)相互作用，从而通过一种称为有偏见的激动剂的过程，导致不同的激动剂指导的基因表达程序。 假设 总的假设是，在给定的细胞类型中，可以产生不同的GR介导的基因表达程序，这取决于激活配体的固有结构及其创造GR独特构象的能力。这改变了与GR结合的强制性辅助因子的补体和化学计量比，从而改变了GR在某些基因启动子上比其他基因启动子更有效地相互作用的能力。 目标 进行“概念验证”研究，以确定GR介导的基因表达偏差； 利用生物信息学方法验证、量化和分析基因表达偏差； 探讨偏置GR激动剂的体外生物活性。 预期结果和发现潜力 这项研究计划将应用生物学、分析和生物信息学方法，建立GR介导的基因表达的基本生物学过程，根据该过程，不同的转录信号由激活配体的固有结构指导。许多配体已被确定具有稳定不同构象的GR的潜力，并通过有偏见的激动剂指导不同的基因表达模式。通过创造一种独特的GR构象，配体应该能够对细胞进行编程，使其优先表达不同的基因群体，从而产生相应的功能结果。建立GR介导的、有偏见的激动论的原则可以外推到其他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。