Role of microRNA-17-92 and PDLIM5 Signaling in Pulmonary Arterial Hypertension
Role of microRNA-17-92 and PDLIM5 Signaling in Pulmonary Arterial Hypertension
批准号:
8964376
负责人:
J. Usha RAJ
金额:
$39.95万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-07-15 至 2019-04-30
关键词:
AccountingArteriesAttenuatedBloodBlood VesselsCellsChronicChronic PhaseClinicalComplexDevelopmentDiseaseDown-RegulationE2F1 geneEventExperimental ModelsFailureFunctional disorderGene ProteinsGenesHeartHumanHypoxiaHypoxia Inducible FactorHypoxia-Inducible Factor PathwayIn VitroKnock-outKnockout MiceLIM DomainLeadLungMicroRNAsMolecularMusNatureOxygen measurement, partial pressure, arterialPathogenesisPathway interactionsPatientsPhasePhenotypePlayProcollagen-Proline DioxygenaseProteinsPublic HealthPulmonary HypertensionPulmonary Vascular ResistancePulmonary artery structureRNARegulationReportingResearchResistanceRoleSeveritiesSideSignal TransductionSmooth Muscle MyocytesStagingStructureTestingTransforming Growth Factor betaUntranslated RNAUp-RegulationVascular remodelingVentriculararterial remodelingdesignin vivoinhibitor/antagonistinsightmouse modelnovelnovel strategiesoverexpressionpressurepreventpublic health relevancepulmonary arterial hypertensionreconstitutionresponse
中文摘要
英文摘要
DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) are small non-coding endogenous RNA molecules that are thought to be involved in the pathogenesis of pulmonary arterial hypertension (PAH) though their exact roles are not known. We found that smooth muscle cell (SMC)-specific knockout of miR-17~92 in mice attenuated hypoxia-induced pulmonary hypertension (PH) and reconstitution of miR-17~92 restored it, indicating an important role for miR-17~92 in pathogenesis of PH. We identified that miR-17~92 directly targets prolyl hydroxylase 2 (PHD2) and PDZ and LIM domain 5 (PDLIM5) proteins. Suppression of miR-17~92 induced PHD2 expression and inhibited HIF activity, induced PDLIM5 expression and decreased TGF-ß/Smad signaling and expression of SMC markers, all of which attenuated PH. SMC-specific knockout of PHD2 and PDLIM5 enhanced hypoxia-induced pulmonary artery remodeling whereas overexpression of PDLIM5 inhibited hypoxia-induced PH. These results indicate that miR-17~92 modulates PH by regulating the expression of PHD2 and PDLIM5. In PASMC in-vitro and mouse lungs in-vivo, chronic hypoxia resulted in a biphasic expression of miR-17~92: an early increase followed by a decrease in expression. We found that miR-17~92 expression was reduced in PASMC isolated from PAH patients and that this reduction in miR-17~92 accounted for the de-differentiated phenotype of the IPAH-PASMC. We speculate that up regulation of miR-17~92 may be a common initial event in the pathogenesis of both human and experimental PH and that the late decrease in miR-17~92 expression may be an adaptive mechanism to inhibit further progression of PH. Our hypothesis is that miR-17~92 initiates the pathogenesis of PAH by: 1) directly suppressing PHD2 to activate the HIF pathway; 2) directly suppressing PDLIM5 to activate the TGF-ß/Smad2/3 pathway. The biphasic nature of miR-17~92 expression in chronic hypoxia is a novel finding and we will investigate its significance and the mechanisms involved. In Specific Aim 1, we will determine the molecular mechanisms by which miR-17~92 and PHD2 regulate hypoxia- induced PH. We will investigate whether PHD2 is a novel direct target of miR-17~92 and the molecular mechanisms by which miR-17~92 and PHD2 regulate HIF activity and PH. Specific Aim 2 is to determine the molecular mechanisms by which miR-17~92 and PDLIM5 regulate hypoxia-induced vascular remodeling and PH. We will investigate whether PDLIM5 is a novel direct target of miR-17~92 and the molecular mechanisms by which PDLIM5 negatively regulates TGF-ß/Smad signaling and inhibits the progression of PH. In Specific Aim 3, we will determine the molecular mechanisms underlining the biphasic expression of miR-17~92 and its implication in PH progression. We will investigate the roles of HIF and E2F1 in up regulation of miR-17~92 in the early phase of chronic hypoxia, the role of p53 in inhibition of miR-17~92 in the late phase of chronic hypoxia, and whether knockout of miR-17~92, PHD2, and PDLIM5 in the late stage of hypoxia diminishes or accentuates PH in mice.
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Role of microRNA-17-92 and PDLIM5 Signaling in Pulmonary Arterial Hypertension
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批准号:9261587
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项目类别:
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资助金额:$39.98万
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财政年份:2015
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负责人:J. Usha RAJ
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依托单位:
MicroRNAs in Regulation of Pulmonary Vascular Smooth Muscle Cell Proliferation
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批准号:8335483
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项目类别:
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资助金额:$7.98万
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财政年份:2011
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负责人:J. Usha RAJ
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依托单位:
MicroRNAs in Regulation of Pulmonary Vascular Smooth Muscle Cell Proliferation
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批准号:8211933
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项目类别:
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资助金额:$7.96万
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财政年份:2011
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负责人:J. Usha RAJ
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依托单位:
Mechanism of cGMP-Mediated Vasodilation in Perinatal Lung
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批准号:6866063
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项目类别:
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资助金额:$3.71万
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财政年份:2004
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负责人:J. Usha RAJ
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依托单位:
PAF and Hypoxia-Induced Pulmonary Hypertension
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批准号:7081273
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项目类别:
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资助金额:$34.56万
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财政年份:2004
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负责人:J. Usha RAJ
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依托单位:
PAF and Hypoxia-Induced Pulmonary Hypertension
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批准号:7236631
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项目类别:
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资助金额:$16.34万
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财政年份:2004
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负责人:J. Usha RAJ
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依托单位:
PAF and Hypoxia-Induced Pulmonary Hypertension
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批准号:7649774
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项目类别:
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资助金额:$17.21万
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财政年份:2004
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负责人:J. Usha RAJ
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依托单位:
PAF and Hypoxia-Induced Pulmonary Hypertension
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批准号:6821517
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项目类别:
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资助金额:$35.39万
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财政年份:2004
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负责人:J. Usha RAJ
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依托单位:
PAF and Hypoxia-Induced Pulmonary Hypertension
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批准号:6908146
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项目类别:
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资助金额:$35.39万
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财政年份:2004
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负责人:J. Usha RAJ
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依托单位:
Functional Heterogeneity of Pulmonary Arteries and Veins
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批准号:7091636
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项目类别:
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资助金额:$44.85万
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财政年份:2003
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负责人:J. Usha RAJ
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依托单位:
Functional Heterogeneity of Pulmonary Arteries and Veins
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批准号:8133028
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项目类别:
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资助金额:$50.39万
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财政年份:2003
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负责人:J. Usha RAJ
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依托单位:
Functional Heterogeneity of Pulmonary Arteries and Veins
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批准号:6708997
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项目类别:
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资助金额:$33.78万
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财政年份:2003
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负责人:J. Usha RAJ
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依托单位:
Functional Heterogeneity of Pulmonary Arteries and Veins
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批准号:7920889
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项目类别:
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资助金额:$50.89万
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财政年份:2003
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负责人:J. Usha RAJ
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依托单位:
Functional Heterogeneity of Pulmonary Arteries and Veins
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批准号:6866062
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项目类别:
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资助金额:$3.14万
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财政年份:2003
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负责人:J. Usha RAJ
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依托单位:
Functional Heterogeneity of Pulmonary Arteries and Veins
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批准号:6803063
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项目类别:
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资助金额:$45.93万
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财政年份:2003
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负责人:J. Usha RAJ
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依托单位:
Functional Heterogeneity of Pulmonary Arteries and Veins
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批准号:6933894
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项目类别:
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资助金额:$45.93万
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财政年份:2003
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负责人:J. Usha RAJ
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依托单位:
Functional Heterogeneity of Pulmonary Arteries and Veins
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批准号:7684661
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项目类别:
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资助金额:$50.42万
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财政年份:2003
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负责人:J. Usha RAJ
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依托单位:
Functional Heterogeneity of Pulmonary Arteries and Veins
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批准号:7531162
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项目类别:
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资助金额:$8.35万
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财政年份:2003
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负责人:J. Usha RAJ
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依托单位:
Functional Heterogeneity of Pulmonary Arteries and Veins
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批准号:7475293
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项目类别:
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资助金额:$48.95万
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财政年份:2003
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负责人:J. Usha RAJ
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依托单位:
CGMP-MEDIATED VASODILATION IN PERINATAL LUNG
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批准号:2693375
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项目类别:
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资助金额:$29.75万
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财政年份:1998
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负责人:J. Usha RAJ
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依托单位:
海外基金