Effects of ozone on CFTR expression and HIF signaling
臭氧对 CFTR 表达和 HIF 信号传导的影响
基本信息
- 批准号:7460713
- 负责人:
- 金额:$ 3.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-07-15 至 2009-07-14
- 项目状态:已结题
- 来源:
- 关键词:AffectAir PollutantsAir PollutionAntibodiesAntioxidantsBindingBiological AssayChromatin StructureChronicChronic Obstructive Airway DiseaseChronic lung diseaseComplexConditionCultured CellsCystic Fibrosis Transmembrane Conductance RegulatorDNA-Binding ProteinsDown-RegulationEnd PointEnvironmental Risk FactorEpithelialEpithelial CellsEpitheliumGenetic TranscriptionGlutathioneGoalsHistonesHomeostasisHypoxemiaHypoxiaHypoxia Inducible FactorImmunohistochemistryIn VitroInjuryIntestinesIon ChannelKidneyLiquid substanceLiverLungLung diseasesMaintenanceMeasurementMediatingMessenger RNAModificationMolecularMusNoseOxidantsOxygen measurement, partial pressure, arterialOzonePathogenesisPhysiologicalProtein AnalysisProteinsReactive Oxygen SpeciesRegulationRepressionRoleSignal PathwaySignal TransductionSiteTestingThinkingTissuesToxic Environmental SubstancesToxincell typechromatin immunoprecipitationcigarette smokingin vitro Assayin vivomRNA Expressionnovelozone exposurepollutantpromoterresearch studyresponsetranscription factor
项目摘要
DESCRIPTION (provided by applicant): Many chronic lung diseases are caused or exacerbated by environmental factors such as cigarette smoke (chronic obstructive pulmonary disease) and air pollutants including ozone. The lung epithelia provides a first line defense against many of these agents. The cystic fibrosis transmembrane conductance regulator (CFTR) serves a pivotal role in normal epithelial homeostasis, including the maintenance of normal glutathione levels in the epithelial lining fluid (ELF), a critical component of the defense against airborne toxins. In chronic lung conditions, the activation of HIP signaling pathways, such as may be caused by tissue hypoxemia, result in the down-regulation of CFTR mRNA and protein levels (as suggested by studies in cell culture and mice). Reactive oxygen species, such as those produced by ozone exposure in the lung, have been shown to activate HIF signaling pathways. CFTR deficiency results in a significantly decreased level of glutathione in the ELF, predisposing the lung to oxidant/antioxidant imbalance and additional injury from environmental toxins. The repression of CFTR by HIF signaling pathways, activated by both hypoxia and ROS from pollutants like ozone, represents a novel mechanism for lung disease pathogenesis. The goals of this proposal are to investigate 1) the specific effects of ozone on HIF signaling and CFTR expression and function and 2) the molecular mechanisms by which ROS- and hypoxia-induced HIF signaling repress CFTR.
描述(由申请人提供):许多慢性肺部疾病是由环境因素引起或加剧的,例如香烟烟雾(慢性阻塞性肺病)和包括臭氧在内的空气污染物。肺上皮细胞提供了针对许多此类物质的第一线防御。囊性纤维化跨膜电导调节器 (CFTR) 在正常上皮稳态中发挥着关键作用,包括维持上皮衬里液 (ELF) 中正常的谷胱甘肽水平,这是防御空气传播毒素的关键组成部分。在慢性肺部疾病中,HIP 信号通路的激活(例如可能由组织低氧血症引起的)会导致 CFTR mRNA 和蛋白质水平下调(如细胞培养和小鼠研究表明)。活性氧,例如肺部臭氧暴露产生的活性氧,已被证明可以激活 HIF 信号通路。 CFTR 缺乏会导致 ELF 中谷胱甘肽水平显着降低,使肺部容易出现氧化/抗氧化失衡以及环境毒素造成的额外损伤。 HIF 信号通路对 CFTR 的抑制是由缺氧和臭氧等污染物中的 ROS 激活的,代表了肺部疾病发病机制的一种新机制。该提案的目标是研究 1) 臭氧对 HIF 信号传导以及 CFTR 表达和功能的具体影响,以及 2) ROS 和缺氧诱导的 HIF 信号传导抑制 CFTR 的分子机制。
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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Jennifer S Guimbellot其他文献
Jennifer S Guimbellot的其他文献
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{{ truncateString('Jennifer S Guimbellot', 18)}}的其他基金
Pharmacometric approaches to precision optimization of ivacaftor response in cystic fibrosis patients
精确优化囊性纤维化患者 ivacaftor 反应的药理学方法
- 批准号:
10349477 - 财政年份:2020
- 资助金额:
$ 3.31万 - 项目类别:
Pharmacometric approaches to precision optimization of ivacaftor response in cystic fibrosis patients
精确优化囊性纤维化患者 ivacaftor 反应的药理学方法
- 批准号:
10549860 - 财政年份:2020
- 资助金额:
$ 3.31万 - 项目类别:
Pharmacometric approaches to precision optimization of ivacaftor response in cystic fibrosis patients
精确优化囊性纤维化患者 ivacaftor 反应的药理学方法
- 批准号:
9891524 - 财政年份:2020
- 资助金额:
$ 3.31万 - 项目类别:
Effects of ozone on CFTR expression and HIF signaling
臭氧对 CFTR 表达和 HIF 信号传导的影响
- 批准号:
7261862 - 财政年份:2006
- 资助金额:
$ 3.31万 - 项目类别:
Effects of ozone on CFTR expression and HIF signaling
臭氧对 CFTR 表达和 HIF 信号传导的影响
- 批准号:
7156671 - 财政年份:2006
- 资助金额:
$ 3.31万 - 项目类别:
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