Testing novel models of glucocorticoid-induced transcription regulation

测试糖皮质激素诱导的转录调控的新模型

基本信息

批准号：
8983936
负责人：
Christopher Vockley
金额：
$ 3.39万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8983936
关键词：
Adrenal Cortex Hormones Alternative Therapies Americas Asthma Binding Binding Sites Biological Biological Assay Biology Cause of Death Cell Nucleus Cells ChIP-seq Chronic Obstructive Airway Disease Clinical Combinatorics DNA DNA Binding Data Dose Elements Enhancers Environment Foundations Gene Activation Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genome Genomics Glucocorticoid Receptor Glucocorticoids Goals Health Hormones Hypersensitivity Investigation Learning Lung Lung diseases Metabolic Minority Modeling Molecular Morphogenesis Mothers Outcome Patients Play Proteins Publishing Regulation Regulatory Element Reporter Research Rheumatoid Arthritis Role Series Signal Transduction Site Specificity Testing Therapeutic Agents Therapeutic Effect Transcription Factor AP-1 Transcriptional Regulation Transplantation Work asthmatic patient base clinical efficacy genome editing glucocorticoid-induced orphan receptor insight novel prenatal public health relevance receptor binding research study respiratory response targeted treatment therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Corticosteroid hormones are important in a wide variety of biological contexts and are widely used as therapeutic agents. The most prevalent uses of corticosteroids in the clinical environment include the treatment of asthma and the prenatal administration of corticosteroids to mothers expecting to deliver babies pre-term, in order to facilitate terminal lung morphogenesis. Despite the broad clinical utility of corticosteroids, not all patients respond to their therapeutic effects. Additionally, off target efects of corticosteroids include metabolic perturbations detrimental to patient health. Our recent research suggests that several novel mechanisms govern the activity and specificity of glucocorticoid (GC) signaling. Specifically, we have demonstrated that the vast minority of glucocorticoid receptor (GR) binding sites controls the majority of GC-induced gene expression. We provide evidence for a novel enhancer-cluster model of GR-induced gene activation. In this proposal we will test our core hypothesis that GR binding at sites that contain the canonical GR binding motif drive the primary transcription response to GCs and that AP1-tethered binding sites proximal to direct GR binding sites act secondarily to modulate the primary GC-induced transcription response. Ultimately understanding the molecular underpinnings that govern the activity of the GR will yield critical insights that could increase the clinical efficacy of GCs amng GC-nonresponsive patients and reduce the off target effects of corticosteroid therapies.

描述（由申请人提供）：皮质类固醇激素在多种生物学背景中都很重要，并且广泛用作治疗剂。皮质类固醇在临床环境中最普遍的用途包括治疗哮喘和给怀孕的母亲产前施用皮质类固醇。尽管皮质类固醇具有广泛的临床用途，但并非所有患者都会对其治疗效果产生反应，从而促进终末期肺部形态发生。我们最近的研究表明，糖皮质激素 (GC) 信号传导的活性和特异性受到新机制的影响，具体而言，我们已经证明少数糖皮质激素受体 (GR) 结合位点控制着大多数 GC。我们为 GR 诱导基因激活的新型增强子簇模型提供了证据，我们将测试我们的核心假设，即 GR 结合在包含典型 GR 结合基序的位点上。 GC 的初级转录反应以及接近直接 GR 结合位点的 AP1 束缚结合位点其次发挥作用来调节初级 GC 诱导的转录反应，最终了解控制 GR 活性的分子基础将产生重要的见解，从而可以提高GC 对 GC 无反应患者的临床疗效，并减少皮质类固醇治疗的脱靶效应。