Hypoxic-Inducible Factors in Neonatal Pulmonary Hypertension
新生儿肺动脉高压的缺氧诱发因素
基本信息
- 批准号:8214146
- 负责人:
- 金额:$ 6.48万
- 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:2011-01-01 至 2012-12-31
- 项目状态:已结题
- 来源:
- 关键词:ABCA3 geneAcuteAdultAdult Respiratory Distress SyndromeAffectAirAlbuminsAlveolarAmniotic FluidAnemiaAngiogenic FactorAnimalsAreaAutopsyBirthBlood CirculationBlood VesselsBlood capillariesBlood flowBlood gasBreathingBronchoalveolar LavageBronchopulmonary DysplasiaCarrier ProteinsCellsCessation of lifeChildChronicDataDevelopmentDiseaseDoseDuctalDuctus ArteriosusEconomic InflationEndothelial CellsEndotheliumEnvironmentEpithelial CellsEpitheliumEquilibriumErythropoietinFaceFetal LungFetusFrequenciesGene ExpressionGene FamilyGenesGrowth and Development functionHomeostasisHyperoxiaHypoxiaHypoxia Inducible FactorInfantInflammationInflammatoryInjuryKnock-outKnowledgeLecithinLeft pulmonary arteryLipidsLungLung ComplianceMeasurementMeasuresMechanicsMessenger RNAModelingNeonatalNewborn InfantOperative Surgical ProceduresOxygenOxygen measurement, partial pressure, arterialPatent Ductus ArteriosusPerinatalPerinatal Pulmonary HypertensionPharmaceutical PreparationsPhenotypePregnancyPremature BirthPremature InfantPrimatesProcessProcollagen-Proline DioxygenaseProductionProteinsPulmonary CirculationPulmonary EdemaPulmonary Gas ExchangePulmonary HypertensionPulmonary artery structureRecombinant ProteinsRelative (related person)RelaxationReportingResearch PersonnelRespiratory distressRespiratory physiologyRoleRouteSignal TransductionStructure of parenchyma of lungSurfaceSystemTerm BirthTherapeuticTherapeutic UsesThird Pregnancy TrimesterTransgenic MiceVascular DiseasesVascular Endothelial Growth FactorsVascular remodelingVasodilationangiogenesisascorbatebasecapillarycofactorcostcytokinefetalhemodynamicshuman NOS3 proteinhypoxia inducible factor 1improvedin uteroin vitro Modelin vivoindexinginhibitor/antagonistinstrumentinstrumentationlipid transportlung developmentlung hypoxiamorphometryneonatal pulmonary hypertensionneonatepersistent pulmonary hypertensionpostnatalprenatalpressureprogramsprotein expressionreceptorrespiratory distress syndromesurfactanttrendvascular bed
项目摘要
Pulmonary hypertension (PHN) in respiratory distress syndrome (RDS) evolving to bronchopulmonary
dysplasia (BPD) results acutely from poor lung inflation and increased blood flow through the patent ductus
arteriosus, and chronically from altered reactivity, vascular remodeling, and hypoplasia of the pulmonary
vascular bed. The lung develops in relative hypoxia compared to 21% 02 seen at normal term delivery and,
especially, to hyperoxia that preterm neonates commonly face. Hypoxia-inducible factors (HIFs) could lower
pulmonary artery pressures by modulating surfactant, ductus arteriosus, and pulmonary vascular
development. Preliminary data show that HIFs can impact lung expansion at birth, expression of
surfactant proteins and lipids, patency of the ductus arteriosus, and angiogenic factors and
processes in developing lungs - all of which canmodify pulmonary hypertension. Further data show
that HIFs are highly expressed and stable in third trimester fetal primate lungs, while one of them, HIF-1a,
declines dramatically after preterm birth. Using cofactors 02, Fe2+, oxoglutarate, and ascorbate, HIF prolyl-
hydroxylases (PHDs) specifically regulate HIFstability. We reported that PHDinhibitors (PHDi)
profoundly alter stability of HIFs and downstream gene expression (VEGF and its receptors) in lung
endothelial and epithelial cells, and fetal lung explants, even in extreme hyperoxia. We hypothesize that
PHDi can decrease PHNby restoring the fetal VEGF/eNOS axis and improving perinatal surfactant
homeostasis. We propose to examine effects of PHDi delivered antenatally or postnatally, and by differing
routes, in ovine models of RDS and persistent PHN in preterm and term ovine models, respectively.
Chronically instrumented fetal/neonatal lambs will have pre- and/or postnatal hemodynamic, blood gas, and
respiratory physiology measurements. In lung tissue from these animals, we will measure HIFs, HIF-
dependent gene products, surfactant proteins and lipids, inflammatory cytokines and cells, and lung
morphometry to assess vascular development and remodeling. Results will provide valuable information
about pathophysiologic roles of HIFs in perinatal PHN and potential therapeutic uses of PHDi in RDS and
PHN.
呼吸窘迫综合征(RDS)发展为支气管肺的肺动脉高压(PHN)
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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Carl W White其他文献
CXCL17 induces activation of human mast cells via MRGPRX2
CXCL17 通过 MRGPRX2 诱导人类肥大细胞激活
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Jie Ding;Christina Hillig;Carl W White;Nithya A Fernandopulle;Holly Anderton;Johannes S Kern;Michael P. Menden;Graham A Mackay - 通讯作者:
Graham A Mackay
3 ROS : reactive oxygen species RT-qPCR : reverse transcription quantitative PCR SM : sulfur mustard SpO 2 : peripheral oxygen saturation tPA : tissue plasminogen activator
3 ROS : 活性氧 RT-qPCR : 逆转录定量 PCR SM : 硫芥 SpO 2 : 外周血氧饱和度 tPA : 组织纤溶酶原激活剂
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Heidi J. Nick;Carly A Johnson;Amber R. Stewart;Sarah Christeson;A. Leslie;Bloomquist;Amanda S. Appel;A. Donkor;L. Veress;B. Logue;E. Preston;Bratcher;Carl W White - 通讯作者:
Carl W White
Carl W White的其他文献
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{{ truncateString('Carl W White', 18)}}的其他基金
New Developments in Chemical Countermeasures: CounterACT 2018
化学对抗新进展:CounterACT 2018
- 批准号:
9490163 - 财政年份:2016
- 资助金额:
$ 6.48万 - 项目类别:
CRITICAL TARGETS IN HYPEROXIC MITOCHONDRIAL INJURY
高氧线粒体损伤的关键目标
- 批准号:
7716163 - 财政年份:2008
- 资助金额:
$ 6.48万 - 项目类别:
Novel antioxidant therapeutics for sulfur mustard toxicity (U54)
针对硫芥毒性的新型抗氧化疗法 (U54)
- 批准号:
7294907 - 财政年份:2006
- 资助金额:
$ 6.48万 - 项目类别:
Novel therapeutics for vesicants and toxic inhaled chemicals (U54)
针对出疱剂和有毒吸入化学品的新型疗法 (U54)
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8737370 - 财政年份:2006
- 资助金额:
$ 6.48万 - 项目类别:
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