Nrf2 as a critical determinant of smooth muscle function
Nrf2 作为平滑肌功能的关键决定因素
基本信息
- 批准号:8625328
- 负责人:
- 金额:$ 40.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-05-01 至 2016-02-29
- 项目状态:已结题
- 来源:
- 关键词:AddressAdhesionsAffectAgonistAllergensAntioxidantsAsthmaBiochemicalBiological MarkersBiomimeticsBlood capillariesBroccoli - dietaryCellsChronicContractsCustomCytometryCytoskeletonDataDevelopmentDiseaseDoseElasticityEnzymesExtracellular MatrixFourier TransformGene DeletionGene ExpressionGene TargetingGenerationsGenesGlutathione DisulfideHumanHydrogen PeroxideIndividualInterventionKnock-outKnowledgeLeadLifeLinkMagnetismMeasuresMechanicsMethodsMicrofluidic MicrochipsMicroscopyModelingMolecularMotionMusMuscle CellsMuscle ContractionMuscle functionNitric Oxide SynthaseNitrogenObstructionOrganOxidation-ReductionOxidative StressOxidative Stress PathwayOxygenPathologyPathway interactionsPatternPeroxonitritePhosphorylationPopulationProtein IsoformsPublic HealthPyroglyphidaeRegimenRegulationResearchRoleSignal PathwaySignal TransductionSmooth MuscleSmooth Muscle MyocytesStructureStructure-Activity RelationshipSulforaphaneT-LymphocyteTherapeutic StudiesTracerTractionUnited Statesairway hyperresponsivenessasthmatic airwayasthmatic patientbasecapillaryconstrictiondesignhuman diseaseinnovationlithographymouse modelnanonanoscalenuclear factor-erythroid 2oxidant stresspublic health relevancerespiratory smooth muscleresponserestorationsmall hairpin RNAtherapeutic effectivenesstranscription factor
项目摘要
DESCRIPTION (provided by applicant): The pathology of chronic asthma shows prominent structural changes in the airway wall, specifically alteration in the extracellular matrix (ECM) and thickening of the airway smooth muscle (ASM). However, how these structural changes affect asthmatic airflow obstruction is not well understood. We are proposing an entirely new experimental approach to elucidate this structure-function relationship that is based on dysfunctional regulation of oxidative stress. We reason that ASM may be a major target of oxidative stress. In support of this paradigm, we have demonstrated that mice, with a deletion of a transcription factor (Nrf2) that regulates several antioxidant genes, are more susceptible to oxidative stress and airway hyperresponsiveness, and that the hyperresponsiveness is primarily attributable to increased ASM contractility. Based on preliminary data showing differential induction of Nrf2-dependent cytoprotective genes and force generation by healthy versus asthmatic human ASM cells, we hypothesize that airflow obstruction in chronic asthma is attributable to defective Nrf2-directed regulation of oxidative stress that leads to abnormal ECM remodeling and increased contractility of the ASM cell. In addition, we hypothesize that stimulation of Nrf2-directed antioxidant pathways by sulforaphane can restore the cytoprotective status conferred by the ECM on ASM and inhibit ASM contraction altogether. To address these hypotheses, we will use UV-assisted capillary force lithography to fabricate micro- and nano-topographically defined substrata that better recapitulate ECM structure and elasticity of the airway wall. Using these biomimetic substrata with variable distribution of ECM patterns and rigidities, we will quantify changes in both structure and function of human ASM cells. For quantitative structural analysis, we will implement the high-throughput custom-built microfluidic devices that allow the in- chip design for culturing live cells. At the single cell level, we will measure changes in ASM stiffness using Magnetic Twisting Cytometry (MTC), contractile force using Fourier Transform Traction Microscopy (FTTM), and discrete molecular-level remodeling dynamics of the cytoskeleton using Spontaneous Nanoscale Tracer Motions (SNTM). With these technical innovations, we will probe the internal network of physical forces within ASM to determine: (Aim 1) the biochemical and mechanical factors that affect ASM contraction; (Aim 2) the molecular link between ASM contraction and Nrf2-directed regulation of oxidative stress; and (Aim 3) the efficacy of targeting Nrf2 pathways to eliminate ASM contraction. Finally, as a proof-of-concept, we will validate the therapeutic effectiveness of sulforaphane (in the form of broccoli sprout extract) in a mouse model with airway hyperresponsiveness induced by house dust mite (HDM). The HDM model is much more relevant to human sensitization and thereby provides a tighter link between what we might discover in the mouse model to human disease. If successful, the knowledge gained from these studies has the potential to redirect our approach to asthma research and therapy, and may lead to the development of new intervention strategies.
PUBLIC HEALTH RELEVANCE: In the past 20 years, asthma cases have more than doubled. Asthma is a debilitating airway disorder and affects some 20 million people in the United States, but remains unexplained. Here we focus on the structure and function of airway smooth muscle - the end organ that leads to airway constriction - and the role for a transcription factor (Nrf2) in the context of airway wall remodeling in chronic asthma.
描述(由申请人提供):慢性哮喘的病理表现为气道壁明显的结构改变,特别是细胞外基质(ECM)的改变和气道平滑肌(ASM)的增厚。然而,这些结构变化如何影响哮喘气流阻塞尚不清楚。我们提出了一种全新的实验方法来阐明这种基于氧化应激功能失调调节的结构-功能关系。我们认为ASM可能是氧化应激的主要靶点。为了支持这一范式,我们已经证明,缺失调控几种抗氧化基因的转录因子(Nrf2)的小鼠更容易受到氧化应激和气道高反应性的影响,而高反应性主要是由于ASM收缩性增加。根据初步数据显示,健康与哮喘人类ASM细胞对nrf2依赖性细胞保护基因和力产生的诱导存在差异,我们假设慢性哮喘中的气流阻塞是由于nrf2定向氧化应激调节缺陷导致的异常ECM重塑和ASM细胞收缩性增加。此外,我们假设萝卜硫素刺激nrf2导向的抗氧化途径可以恢复ECM对ASM的细胞保护作用,并完全抑制ASM收缩。为了解决这些假设,我们将使用紫外辅助毛细管力光刻技术来制造微观和纳米形貌定义的基质,以更好地再现ECM结构和气道壁的弹性。利用这些具有可变ECM模式和刚度分布的仿生基质,我们将量化人类ASM细胞结构和功能的变化。对于定量结构分析,我们将实施高通量定制微流控装置,允许芯片内设计培养活细胞。在单细胞水平上,我们将使用磁扭转细胞术(MTC)测量ASM刚度的变化,使用傅立叶变换牵引显微镜(FTTM)测量收缩力的变化,并使用自发纳米级示踪运动(SNTM)测量细胞骨架的离散分子水平重塑动力学。通过这些技术创新,我们将探索ASM内部的物理力量网络,以确定:(目标1)影响ASM收缩的生化和机械因素;(Aim 2) ASM收缩与nrf2调控氧化应激之间的分子联系;以及(Aim 3)靶向Nrf2通路消除ASM收缩的功效。最后,作为概念验证,我们将在屋尘螨(HDM)诱导的气道高反应性小鼠模型中验证萝卜硫素(以西兰花芽提取物的形式)的治疗效果。HDM模型与人类致敏性更相关,因此在我们可能在小鼠模型中发现的与人类疾病之间提供了更紧密的联系。如果成功,从这些研究中获得的知识有可能改变我们对哮喘研究和治疗的方法,并可能导致新的干预策略的发展。
项目成果
期刊论文数量(0)
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Steven S An其他文献
Mendelian Randomization Analysis Reveals a Complex Genetic Interplay Among Atopic Dermatitis, Asthma, and GERD.
孟德尔随机分析揭示了特应性皮炎、哮喘和胃食管反流病之间复杂的遗传相互作用。
- DOI:
- 发表时间:
2022 - 期刊:
- 影响因子:24.7
- 作者:
K. Ahn;R. Penn;S. Rattan;R. Panettieri;B. Voight;Steven S An - 通讯作者:
Steven S An
Steven S An的其他文献
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{{ truncateString('Steven S An', 18)}}的其他基金
Targeting T2 inflammation-evoked mechanical endotypes of ASM shortening in asthma
靶向哮喘中 ASM 缩短的 T2 炎症诱发机械内型
- 批准号:
10657988 - 财政年份:2023
- 资助金额:
$ 40.18万 - 项目类别:
Nrf2 as a critical determinant of smooth muscle function
Nrf2 作为平滑肌功能的关键决定因素
- 批准号:
8083135 - 财政年份:2011
- 资助金额:
$ 40.18万 - 项目类别:
Nrf2 as a critical determinant of smooth muscle function
Nrf2 作为平滑肌功能的关键决定因素
- 批准号:
8260499 - 财政年份:2011
- 资助金额:
$ 40.18万 - 项目类别:
Nrf2 as a critical determinant of smooth muscle function
Nrf2 作为平滑肌功能的关键决定因素
- 批准号:
8434873 - 财政年份:2011
- 资助金额:
$ 40.18万 - 项目类别:
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