microRNA-25 attenuates allergic inflammation by altering airway smooth muscle phenotype and function
microRNA-25 attenuates allergic inflammation by altering airway smooth muscle phenotype and function
批准号:
9029194
负责人:
Cherie Singer
金额:
$35.53万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-02-01 至 2019-12-31
关键词:
AcuteAddressAffectAgonistAllergic inflammationAsthmaAttenuatedBiological AssayCell ProliferationCellsChronicContractile ProteinsCoupledDataDevelopmentDiseaseDisease modelEosinophiliaEpigenetic ProcessEpitheliumEventExhibitsExtracellular MatrixExtrinsic asthmaFibrosisFutureGene ExpressionGene SilencingGene TargetingGeneticGoalsGrowthHealthHumanImmunoblottingImmunohistochemistryIn VitroInflammationInflammation MediatorsInflammatoryInflammatory ResponseLaboratoriesLinkLiquid substanceLungMediatingMicroRNAsModelingMolecularMonitorMusObstructionOvalbuminPathogenesisPhenotypeProliferating Cell Nuclear AntigenRegulator GenesRespiratory physiologyRoleSignal PathwaySignal TransductionSignaling ProteinSliceSmooth MuscleSmooth Muscle Actin Staining MethodSmooth Muscle MyocytesStimulusStructure of parenchyma of lungSymptomsTestingTherapeuticTransgenic Miceairway hyperresponsivenessairway inflammationairway obstructionairway remodelingasthmaticasthmatic airwayasthmatic patientbasegain of functionhuman diseasein vivoinflammatory lung diseaseinhibitor/antagonistknock-downlentiviral-mediatedmTOR Signaling Pathwaymouse modelmuscle formmuscular structurenovelnovel therapeuticsoutcome forecastresearch studyrespiratory smooth muscleresponsetool
中文摘要
英文摘要
DESCRIPTION (provided by applicant): In vitro studies have established that airway smooth muscle (ASM) cells exhibit phenotypic plasticity in response to inflammatory events mediated by transcriptional and post-transcriptional mechanisms that have not been fully elucidated. microRNA (miRNA)-mediated gene silencing has emerged as an regulator of gene expression and studies of miRNA function in ASM hold promise for the development of novel miRNA-based tools for prognosis and therapy. The long-term goal of our studies is to identify the miRNA-mediated gene- silencing mechanisms determining ASM cell phenotype in asthma. Our laboratory was the first to characterize miRNA expression in ASM following a pro-inflammatory stimulus and identified miR-25 as a target of the inflammatory response that regulates plasticity of ASM cells. This proposal will test the hypothesis that expression of miR-25 attenuates allergic asthma pathogenesis by altering ASM phenotype. In Specific Aim 1, we will determine whether miR-25 expression in a mouse model of allergic inflammation attenuates hyperreactivity, remodeling and alters ASM contractile force using a unique transgenic mouse model of smooth muscle-targeted miR-25 expression. These mice will be used to assess the effects of miR-25 on AHR, remodeling and ASM contractility following acute and chronic models of ovalbumin-sensitization and challenge. In Specific Aim 2, we will study the effect of smooth muscle-targeted miR-25 expression on increased ASM mass in vivo following acute and chronic ovalbumin-sensitization and challenge by assessing proliferative markers and mitogenic signaling pathways to address the molecular mechanisms underlying this miR-25 function. In Specific Aim 3, we will determine whether miR-25 affects the phenotype of asthmatic ASM cells using gain and loss of miR-25 function studies, as well as effects on identified targets of miR-25 mediated gene-silencing. This unique experimental approach, coupled with correlations in human diseased cells, will provide mechanistic data describing miR-25 function in the lung and be an essential step towards developing novel therapeutic strategies targeting miRNA in asthma.
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会议论文
COBRE: UNR: MOLECULAR BIOLOGY CORE (B)
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批准号:7959485
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项目类别:
-
资助金额:$24.04万
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财政年份:2009
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负责人:Cherie Singer
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依托单位:
COBRE: UNR: MOLECULAR BIOLOGY CORE (B)
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批准号:7720387
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项目类别:
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资助金额:$21.43万
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财政年份:2008
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负责人:Cherie Singer
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依托单位:
Interferon regulation of T-bet in airway smooth muscle
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批准号:7483034
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项目类别:
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资助金额:$12.54万
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财政年份:2005
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负责人:Cherie Singer
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依托单位:
Interferon regulation of T-bet in airway smooth muscle
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批准号:7269459
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项目类别:
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资助金额:$12.27万
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财政年份:2005
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负责人:Cherie Singer
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依托单位:
Interferon regulation of T-bet in airway smooth muscle
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批准号:7127676
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项目类别:
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资助金额:$12.01万
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财政年份:2005
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负责人:Cherie Singer
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依托单位:
Interferon regulation of T-bet in airway smooth muscle
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批准号:6945069
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项目类别:
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资助金额:$11.75万
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财政年份:2005
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负责人:Cherie Singer
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依托单位:
IL1 BETA AND MAP KINASE MEDIATED AIRWAY RESPONSES
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批准号:6183689
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项目类别:
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资助金额:$3.75万
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财政年份:2000
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负责人:Cherie Singer
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依托单位:
IL1 BETA AND MAP KINASE MEDIATED AIRWAY RESPONSES
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批准号:6078026
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项目类别:
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资助金额:$3.17万
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财政年份:1999
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负责人:Cherie Singer
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依托单位:
IL1 BETA AND MAP KINASE MEDIATED AIRWAY RESPONSES
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批准号:2710183
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项目类别:
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资助金额:$2.5万
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财政年份:1998
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负责人:Cherie Singer
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依托单位:
海外基金