Mechanisms and Consequences of Gene Induction by Glucocorticoids in Airway Smooth Muscle
糖皮质激素在气道平滑肌中基因诱导的机制和后果
基本信息
- 批准号:10446915
- 负责人:
- 金额:$ 75.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-15 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAdvanced DevelopmentAmericanAnti-Inflammatory AgentsApplications GrantsAsthmaBindingBiochemicalBioinformaticsBiological AssayCellsChIP-seqChromatinChromatin LoopClinicalComplexDNADNA SequenceDataData SetDiseaseEnhancersExhibitsFamilyFunctional disorderGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGenomic approachGenomicsGlucocorticoid ReceptorGlucocorticoidsGoalsHealth Care CostsHumanImmuneInfectionInflammationInflammatoryInhalationKnowledgeLigand BindingLigandsLinkLungMediatingMethodsModelingMolecularMolecular ConformationMuscle functionOdds RatioPathogenesisPathway interactionsPatientsPersonsPharmaceutical PreparationsPharmacogenomicsPharmacologyRNAReceptor SignalingRegulationReporterRepressionResearchResponse ElementsRiskSignal PathwaySignal TransductionSingle Nucleotide PolymorphismSiteSliceSmall Interfering RNASteroidsSymptomsSystemic TherapyTestingTherapeuticTherapeutic EffectTissuesTranscriptTranscriptional RegulationViralanalysis pipelineasthma exacerbationasthmatic patientbasecell typechromosome conformation capturecytokinegene inductiongenetic associationgenetic signaturegenome-widegenomic signatureglycosyltransferaseimprovedknock-downmembernovelnovel therapeuticspromoterreceptorreceptor bindingrespiratory smooth muscleresponseside effecttherapeutic evaluationtranscription factortranslational approachtranslational modelvirtual
项目摘要
Glucocorticoids (GCs, generically known as “steroids”) are exceptionally effective drugs in the control of a wide
variety of immune-mediated diseases, including asthma. They are also used to treat viral-induced inflammation
in the context of asthma exacerbations. Through reducing inflammation in tissues such as airway smooth muscle
(ASM), inhaled GCs are very effective in the majority of asthma patients, whereas systemic therapy, which
causes side effects, is used to treat asthma exacerbations. Despite using best therapies, over one million
Americans continue to be afflicted with difficult-to-control asthma and frequent exacerbations. Thus, new
pharmacologic approaches aimed at steroid signaling mechanisms in the lung, including ASM, are urgently
needed to improve treatment for asthma.
GCs primary biochemical function is to bind to the GC receptor (GR), leading to regulation of transcription
directly by GR, which is a transcription factor. ASM is a key target tissue of GCs in asthma, and ASM exhibits
hyper-contractility, remodeling and exuberant cytokine expression in asthma. Previous efforts to exploit steroid-
controlled pathways as a method to improve asthma therapies directed at ASM have been predicated on the so
called “transrepression” model of GR activity, in which GR is thought to reduce inflammation by antagonistic
tethering to pro-inflammatory transcription factors such as NFkB. Entirely contrary to dogma, this grant
application is focused instead on transcriptional induction by GR and cooperation between GR and NFkB. Our
preliminary data implicate GR-NFkB cooperation as central to controlling inflammation in ASM, thus likely
contributing significantly to efficacy of steroids. Mechanistically, our data suggest this pathway involves
transcription of enhancer RNAs and formation of chromatin loops, and our data also suggest this mechanism is
druggable. Based on our promising findings on GR-induced pathways, we have also created a novel method to
interrogate GR-induced enhancer RNA signatures for genetic links to asthma. Our overarching hypothesis is
that GR-mediated transcriptional induction and GR-NFkB cooperation in ASM is crucial for steroid efficacy in
asthma and these pathways are linked to risk of developing asthma. We will test this hypothesis with three
specific aims, which will also address crucial molecular knowledge gaps. In Aim 1, we will determine the
comprehensive set of enhancer RNAs that are induced cooperatively by GR/NFkB and determine if these
enhancer RNAs loop to the promoters of anti-inflammatory genes. In Aim 2, we will determine the DNA sequence
requirements and additional factors involved in cooperative regulation by GR and NFkB, and we will test the
therapeutic relevance of this pathway in translational models. In Aim 3, we will identify novel genetic associations
between SNPs, GR-induced enhancers and asthma, and we will determine the relevance of these SNPs to GR
signaling and ASM function.
糖皮质激素(GC,一般称为"类固醇")是控制广泛的
各种免疫介导的疾病,包括哮喘。它们也用于治疗病毒引起的炎症
在哮喘急性发作的情况下。通过减少气道平滑肌等组织的炎症
(ASM),吸入性GC对大多数哮喘患者非常有效,而全身治疗,
会引起副作用,用于治疗哮喘恶化。尽管使用了最好的疗法,
美国人继续受到难以控制的哮喘和频繁恶化的折磨。因此,新
迫切需要针对肺部类固醇信号传导机制(包括ASM)的药理学方法
需要改善哮喘的治疗。
GC的主要生化功能是与GC受体(GR)结合,从而调节转录
GR是一种转录因子。在哮喘中,ASM是GC的关键靶组织,并且ASM表现出
哮喘中的过度收缩、重塑和细胞因子表达旺盛。以前开发类固醇的努力-
控制途径作为一种方法,以改善哮喘治疗针对ASM已被预测的基础上,
称为GR活性的"反式阻遏"模型,其中GR被认为通过拮抗性抑制来减少炎症,
与促炎性转录因子如NF κ B连接。与教条完全相反,这项赠款
相反,应用集中于GR的转录诱导以及GR和NF κ B之间的合作。我们
初步数据暗示GR-NFkB合作是控制ASM炎症的核心,因此可能
对类固醇的功效有显著的贡献。从机制上讲,我们的数据表明,这一途径涉及
增强子RNA的转录和染色质环的形成,我们的数据也表明这种机制是
可下药的基于我们对GR诱导途径的有希望的发现,我们还创造了一种新的方法,
研究GR诱导增强子RNA信号与哮喘的遗传联系。我们的首要假设是
GR介导的转录诱导和GR-NFkB在ASM中的合作对于类固醇在
哮喘,这些途径与患哮喘的风险有关。我们将用三个例子来检验这个假设。
具体目标,这也将解决关键的分子知识差距。在目标1中,我们将确定
GR/NFkB协同诱导的一组全面的增强子RNA,并确定这些增强子RNA是否
增强子RNA环到抗炎基因的启动子。在目标2中,我们将确定DNA序列
GR和NFkB合作调节中涉及的要求和其他因素,我们将测试
这一途径在翻译模型中的治疗相关性。在目标3中,我们将确定新的遗传关联
SNPs、GR诱导的增强子和哮喘之间的关系,我们将确定这些SNPs与GR的相关性,
信号和ASM功能。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ANTHONY N GERBER其他文献
ANTHONY N GERBER的其他文献
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{{ truncateString('ANTHONY N GERBER', 18)}}的其他基金
Aspen Lung Conference: Asthma: Pathogenesis, Phenotypes, Therapies and Gaps
阿斯彭肺部会议:哮喘:发病机制、表型、治疗方法和差距
- 批准号:
10680832 - 财政年份:2023
- 资助金额:
$ 75.96万 - 项目类别:
Maladaptive epigenetic control of MUC5B transcription in pulmonary fibrosis
肺纤维化中 MUC5B 转录的适应不良表观遗传控制
- 批准号:
10627598 - 财政年份:2023
- 资助金额:
$ 75.96万 - 项目类别:
Role of Klf15 in airway smooth muscle and the response to glucocorticoids
Klf15 在气道平滑肌中的作用以及对糖皮质激素的反应
- 批准号:
8459449 - 财政年份:2012
- 资助金额:
$ 75.96万 - 项目类别:
Role of Klf15 in airway smooth muscle and the response to glucocorticoids
Klf15 在气道平滑肌中的作用及对糖皮质激素的反应
- 批准号:
8645718 - 财政年份:2012
- 资助金额:
$ 75.96万 - 项目类别:
Mechanisms and Consequences of Gene Induction by Glucocorticoids in Airway Smooth Muscle
糖皮质激素在气道平滑肌中基因诱导的机制和后果
- 批准号:
10641892 - 财政年份:2012
- 资助金额:
$ 75.96万 - 项目类别:
Role of Klf15 in airway smooth muscle and the response to glucocorticoids
Klf15 在气道平滑肌中的作用及对糖皮质激素的反应
- 批准号:
8826799 - 财政年份:2012
- 资助金额:
$ 75.96万 - 项目类别:
Role of Klf15 in airway smooth muscle and the response to glucocorticoids
Klf15 在气道平滑肌中的作用以及对糖皮质激素的反应
- 批准号:
8298027 - 财政年份:2012
- 资助金额:
$ 75.96万 - 项目类别:
Gli1 in murine lung development and differentiation
Gli1 在小鼠肺发育和分化中的作用
- 批准号:
6956616 - 财政年份:2005
- 资助金额:
$ 75.96万 - 项目类别:
Gli1 in murine lung development and differentiation
Gli1 在小鼠肺发育和分化中的作用
- 批准号:
7254125 - 财政年份:2005
- 资助金额:
$ 75.96万 - 项目类别:
Gli1 in murine lung development and differentiation
Gli1 在小鼠肺发育和分化中的作用
- 批准号:
8002377 - 财政年份:2005
- 资助金额:
$ 75.96万 - 项目类别:
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