Integrated miRNA regulation of Nox4 and cellular redox state in vascular disease
血管疾病中 Nox4 和细胞氧化还原状态的整合 miRNA 调节
基本信息
- 批准号:9316697
- 负责人:
- 金额:$ 29.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-18 至 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:ApoptosisBiologicalBlood VesselsCardiovascular DiseasesCarotid ArteriesCell Differentiation processCell physiologyCellsCellular biologyCouplesDataDevelopmentDifferentiation AntigensDiseaseDisulfidesEndoplasmic ReticulumEventFoundationsFutureGene ExpressionGenesGenetic TranscriptionGlutathioneGoalsHomeostasisHumanHydrogen PeroxideHyperplasiaIndividualInflammationInjuryIon ChannelMalignant NeoplasmsMediatingMessenger RNAMicroRNAsMitochondriaMolecularMuscle CellsNADPH OxidaseOrganellesOxidantsOxidasesOxidation-ReductionOxidative StressPhenotypePilot ProjectsProtein IsoformsProteinsRNA SplicingReactionReactive Oxygen SpeciesReceptor Protein-Tyrosine KinasesRegulationReportingResearchSecond Messenger SystemsSignal TransductionSignal Transduction PathwaySmooth Muscle MyocytesSulfhydryl CompoundsSumSystemTestingVascular DiseasesVascular Smooth MuscleWorkin vivoinnovationinsightnoveloxidationprogramspublic health relevanceresponseresponse to injurysenescencetherapeutic target
项目摘要
DESCRIPTION (provided by applicant): It is the integration of both redox signaling and the intracellular redox state that determines cellular response by coordinating multiple signaling networks. The long-term goal of our research program is to understand how NADPH oxidases can be manipulated to treat cardiovascular diseases. We have reported that Nox4 NADPH oxidase modifies diverse cellular responses. However, the molecular mechanisms by which Nox4 regulate cellular functions are poorly understood. Nox4 is expressed in cellular organelles whose functions are susceptible to changes in the redox potential. In contrast to the other Nox homologs, it is unlikely that Nox4-derived reactive oxygen species function as second messengers since 1) Nox4 is constitutively active; 2) activation of Nox4 is primarily regulated by its expression level; and 3) the reaction between thiols and H2O2 (the primary product of Nox4) is too slow to be of biological relevance. In pilot studies, we made the novel observations that 1)
microRNA-9 (miR-9) is a novel regulator of Nox4 expression; 2) miR-25 induces expression of miR-9; 3) miR-9 elicits changes in Nox4 mRNA splicing; 4) miR-25 and miR-9 levels increase following vascular injury; and 5) changes in Nox4 levels modify the cellular glutathione redox potential and protein thiol status. We therefore hypothesize that miRNA-mediated changes in Nox4 expression dynamically regulate the cellular redox state and coordinate the expression of genes implicated in the development of vascular disease. Aim 1 will test the hypothesis that miR-induced miR expression mediates changes in Nox4 levels, cellular localization, and SMC activation. We will first determine the mechanism by which both miR-25 and miR-9 are required for decreasing Nox4 protein levels. We will then test the hypothesis that miR-9 alters the splice isoform profile and subcellular distribution of Nox4. Next, we will explore the mechanism by which miR-25 induces miR-9 expression. Finally, we will determine whether miR-9 modifies vascular smooth muscle cell (SMC) differentiation and the vascular response to injury. Aim 2 will test the hypothesis that Nox4 dynamically regulates the cellular redox state and transcriptional activity in cultured SMC and in the vessel wall. Proposed studies will determine the effect of changes in Nox4 expression on cellular thiol-disulfide status, the redox potential in different cellular compartments, and on the transcription of redox-sensitive genes. In vivo studies will explore how changes in SMC Nox4 modify vascular redox state and neointimal hyperplasia. This proposal is innovative in that we introduce a new paradigm whereby Nox4 acts as a redox rheostat, establishing the thiol oxidation state of cellular proteins to coordinate signaling event. These data may provide a unifying mechanism for the diverse and ambiguous functions of Nox4 across multiple biologic systems. Our data will be the first to provide evidence that one miRNA is indirectly induced by another miRNA. Finally, our findings will provide crucial insights into whether Nox4, miR-9, and miR-25 are therapeutic targets in vascular disease.
描述(由申请人提供):氧化还原信号传导和细胞内氧化还原状态的整合通过协调多个信号传导网络来决定细胞反应。我们研究计划的长期目标是了解如何操纵 NADPH 氧化酶来治疗。我们已经报道,Nox4 NADPH 氧化酶可以改变多种细胞反应。然而,Nox4 调节细胞功能的分子机制尚不清楚。与其他 Nox 同系物相比,Nox4 衍生的活性氧不太可能作为第二信使,因为 1) Nox4 具有组成型活性;2) Nox4 的激活主要受到调节。其表达水平;3) 硫醇和 H2O2(Nox4 的主要产物)之间的反应太慢,不具有生物学意义。那个 1)
microRNA-9 (miR-9) 是 Nox4 表达的新型调节因子;2) miR-25 诱导 miR-9 的表达;3) miR-9 引起 Nox4 mRNA 剪接的变化;血管损伤后增加;5) Nox4 水平的变化改变细胞谷胱甘肽氧化还原电位和蛋白质硫醇状态,因此我们寻找 miRNA 介导的 Nox4 表达变化。动态调节细胞氧化还原状态并协调与血管疾病发展有关的基因表达。目标 1 将检验 miR 诱导的 miR 表达介导 Nox4 水平、细胞定位和 SMC 激活的变化的假设。然后我们将检验 miR-25 和 miR-9 降低 Nox4 蛋白水平所需的机制,即 miR-9 改变 Nox4 的剪接亚型谱和亚细胞分布。接下来,我们将探讨 miR-25 诱导 miR-9 表达的机制,最后,我们将确定 miR-9 是否改变血管平滑肌细胞 (SMC) 分化以及血管对损伤的反应,目的 2 将检验这一假设。 Nox4 动态调节培养的 SMC 和血管壁中的细胞氧化还原状态和转录活性。拟议的研究将确定 Nox4 表达的变化对细胞硫醇二硫化物状态(氧化还原电位)的影响。体内研究将探索 SMC Nox4 的变化如何改变血管氧化还原状态和新内膜增生,因为我们引入了一种新的范例,其中 Nox4 充当氧化还原变阻器。 ,建立细胞蛋白质的硫醇氧化态以协调信号传导事件,这些数据可能为跨多个生物系统的 Nox4 的多样化和模糊功能提供统一的机制。提供证据表明一种 miRNA 是由另一种 miRNA 间接诱导的。最后,我们的研究结果将为了解 Nox4、miR-9 和 miR-25 是否是血管疾病的治疗靶点提供重要见解。
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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FRANCIS J MILLER其他文献
FRANCIS J MILLER的其他文献
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{{ truncateString('FRANCIS J MILLER', 18)}}的其他基金
Regulation of the Nox1 NADPH Oxidase in Vascular Smooth Muscle Cells
血管平滑肌细胞中 Nox1 NADPH 氧化酶的调节
- 批准号:
8330396 - 财政年份:2012
- 资助金额:
$ 29.99万 - 项目类别:
Regulation of the Nox1 NADPH Oxidase in Vascular Smooth Muscle Cells
血管平滑肌细胞中 Nox1 NADPH 氧化酶的调节
- 批准号:
8698326 - 财政年份:2012
- 资助金额:
$ 29.99万 - 项目类别:
Regulation of the Nox1 NADPH Oxidase in Vascular Smooth Muscle Cells
血管平滑肌细胞中 Nox1 NADPH 氧化酶的调节
- 批准号:
8452589 - 财政年份:2012
- 资助金额:
$ 29.99万 - 项目类别:
Regulation of the Nox1 NADPH Oxidase in Vascular Smooth Muscle Cells
血管平滑肌细胞中 Nox1 NADPH 氧化酶的调节
- 批准号:
9138279 - 财政年份:2012
- 资助金额:
$ 29.99万 - 项目类别:
Glutathione Peroxidase & Redox State in Atherosclerosis
谷胱甘肽过氧化物酶
- 批准号:
7840754 - 财政年份:2009
- 资助金额:
$ 29.99万 - 项目类别:
Glutathione Peroxidase & Redox State in Atherosclerosis
谷胱甘肽过氧化物酶
- 批准号:
7122935 - 财政年份:2005
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$ 29.99万 - 项目类别:
Glutathione Peroxidase & Redox State in Atherosclerosis
谷胱甘肽过氧化物酶
- 批准号:
6962111 - 财政年份:2005
- 资助金额:
$ 29.99万 - 项目类别:
Glutathione Peroxidase & Redox State in Atherosclerosis
谷胱甘肽过氧化物酶
- 批准号:
7468505 - 财政年份:2005
- 资助金额:
$ 29.99万 - 项目类别:
Glutathione Peroxidase & Redox State in Atherosclerosis
谷胱甘肽过氧化物酶
- 批准号:
7278644 - 财政年份:2005
- 资助金额:
$ 29.99万 - 项目类别:
Glutathione Peroxidase & Redox State in Atherosclerosis
谷胱甘肽过氧化物酶
- 批准号:
7671263 - 财政年份:2005
- 资助金额:
$ 29.99万 - 项目类别:
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