Leveraging multiomics and advanced mouse models to delineate mechanisms underlying sex‐specific differences in recovery and repair after neonatal hyperoxia exposure in the developing lung
利用多组学和先进的小鼠模型来描绘新生儿肺发育中高氧暴露后恢复和修复的性别特异性差异的潜在机制
基本信息
- 批准号:10578175
- 负责人:
- 金额:$ 41.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-15 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAddressAlveolarAttenuatedAutomobile DrivingBioinformaticsBiometryBlood VesselsBronchopulmonary DysplasiaCell Surface ReceptorsCellsChronicClinicalDataDevelopmentDevelopmental BiologyDown-RegulationEndothelial CellsEndotheliumExposure toFamilyFemaleFibrosisFoundationsFutureGenetic TranscriptionHumanHyperoxiaImpairmentIn VitroIncidenceKnowledgeLaboratoriesLigandsLungLung diseasesMediatingMesenchymalMessenger RNAMicroRNAsMolecularMorbidity - disease rateMusNational Heart, Lung, and Blood InstituteNeonatalNeonatal Hyperoxic InjuryNeonatologyNewborn InfantOxygenPathogenesisPathologicPathway interactionsPhenotypePhysiciansPhysiologicalPremature InfantPulmonary FibrosisPulmonary HypertensionPulmonary PathologyRecoveryReporterRiskRoleScientistSeedsSex DifferencesSignal TransductionTestingTranscriptVascularizationangiogenesiscostcrosslinking and immunoprecipitation sequencingdefined contributionimprovedin vivoinjury and repairlung developmentlung injurymalemouse geneticsmouse modelmultiple omicsneonatal humanneonatal miceneonatenotch proteinnoveloverexpressionpostnatalpre-clinicalprematurepremature lungspreservationpreterm newbornpreventpulmonary functionpulmonary vascular disorderrepairedsexsexual dimorphismtherapeutic targettranscriptometreatment strategy
项目摘要
Bronchopulmonary dysplasia (BPD) is a debilitating lung disease with long-term
consequences and is one of the most common causes for morbidity in premature
neonates. Postnatal exposure to high concentrations of oxygen (hyperoxia) contributes
to the development of BPD. Despite the well-established sex-specific differences in the
incidence of BPD and impaired lung function in males, the molecular mechanism(s)
behind these are not completely understood. Our laboratory has been focused on the
study of sex-specific differences in neonatal hyperoxic lung injury. Endothelial to
mesenchymal transition (EndoMT) contributes to the development of pathologic
pulmonary fibrosis, but the role of EndoMT in BPD has not been determined. Critically,
we have found that neonatal female mice show decreased expression of pro-fibrotic
markers and improved alveolarization and pulmonary vascular development compared
to their male littermates in a murine model of BPD. Furthermore, we show pre-clinical
and clinical evidence of Endo-MT in BPD. Analysis of the pulmonary transcriptome
identified the anti-fibrotic miRNA, miR-30a, as one of the candidates driving these sex-
specific differences. Compellingly, the female advantage in alveolarization and
vascular development is lost in miR30a-/- mice and miR30a expression is decreased in
human BPD lungs. miR30a inhibits both the transcriptional regulator Snai1, as well as
Dll4 (which encodes a Notch ligand). Activation of Snai1 and Dll4/Notch pathway
promote fibrosis through EndoMT. We hypothesize that in hyperoxic female neonates,
miR30a attenuates pathological fibrosis in the developing lung through downregulation
of Dll4-Notch signaling and decreased Snai1 expression. The above hypothesis will be
tested by the following specific aims: Aim 1: Define the contribution of EndoMT and miR-
30a in neonatal hyperoxic lung injury. Aim 2: Determine if miR-30a represses EndoMT
and BPD in females by repressing endothelial Dll4-Notch signaling. Aim 3: Determine if
miR-30a mediated suppression of endothelial Snail1 impacts hyperoxia-induced
EndoMT in BPD. This proposal will address knowledge gaps in the molecular
mechanisms behind the sexual divergent incidence of bronchopulmonary dysplasia and
lay the foundation for future sex-specific treatment strategies.
摘要支气管肺发育不良(Bpd)是一种慢性、慢性、衰弱的肺部疾病。
它是早产儿发病率最常见的原因之一
新生儿。出生后暴露在高浓度氧气(高氧血症)中
为BPD的发展做出贡献。尽管在性别上存在着明显的差异
男性BPD和肺功能损害的发生率及其分子机制(S)
这些背后的原因还没有完全弄清楚。我们的实验室一直专注于
新生儿高氧性肺损伤的性别差异研究内皮细胞到
间充质转化(EndoMT)在病理发展中的作用
肺纤维化,但内源性MT在BPD中的作用尚未确定。关键是,
我们发现新生的雌性小鼠表现出促纤维化的表达减少
标记物与改善肺泡化和肺血管发育的比较
在BPD的小鼠模型中给它们的雄性后代。此外,我们还展示了临床前
以及BPD患者Endo-MT的临床证据。肺组织转录组分析
发现了抗纤维化的miRNA miR-30a,作为驱动这些性行为的候选基因之一
具体区别。令人信服的是,女性在牙槽化和牙槽化方面的优势
MiR30a-/-小鼠血管发育丧失,miR30a表达减少
人类BPD肺。MiR30a既抑制转录调控因子Snai1,也抑制
DLL4(编码Notch配体)。Snai1和Dll4/Notch通路的激活
通过血管内皮细胞移植促进纤维化。我们假设,在高氧血症的女性新生儿中,
MiR30a通过下调表达减轻发育中肺的病理性纤维化
DLL4-Notch信号转导和Snai1表达降低。上述假设将是
通过以下具体目标进行测试:目标1:确定EndoMT和miR的贡献--
新生儿高氧性肺损伤30A。目标2:确定miR-30a是否抑制EndoMT
并通过抑制内皮细胞DLL4-Notch信号在女性中表达BPD。目标3:确定是否
MIR-30a介导的内皮细胞Snail1抑制对高氧诱导的影响
EndoMT,单位为Bpd。这项提议将解决分子中的知识空白问题
支气管肺发育不良与性别差异发病机制的研究
为未来针对性别的治疗策略奠定基础。
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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Krithika Lingappan其他文献
Krithika Lingappan的其他文献
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{{ truncateString('Krithika Lingappan', 18)}}的其他基金
Leveraging multiomics and advanced mouse models to delineate mechanisms underlying sex‐specific differences in recovery and repair after neonatal hyperoxia exposure in the developing lung
利用多组学和先进的小鼠模型来描绘新生儿肺发育中高氧暴露后恢复和修复的性别特异性差异的潜在机制
- 批准号:
10161856 - 财政年份:2020
- 资助金额:
$ 41.37万 - 项目类别:
Sex as biological variable in Bronchopulmonary Dysplasia: Role of the Notch pathway
性别作为支气管肺发育不良的生物学变量:Notch 通路的作用
- 批准号:
10578253 - 财政年份:2020
- 资助金额:
$ 41.37万 - 项目类别:
Leveraging multiomics and advanced mouse models to delineate mechanisms underlying sex‐specific differences in recovery and repair after neonatal hyperoxia exposure in the developing lung
利用多组学和先进的小鼠模型来描绘新生儿肺发育中高氧暴露后恢复和修复的性别特异性差异的潜在机制
- 批准号:
10619663 - 财政年份:2020
- 资助金额:
$ 41.37万 - 项目类别:
Mechanisms of sex differences in neonatal pulmonary oxygen toxicity
新生儿肺氧中毒的性别差异机制
- 批准号:
10447105 - 财政年份:2019
- 资助金额:
$ 41.37万 - 项目类别:
Mechanisms of sex differences in neonatal pulmonary oxygen toxicity
新生儿肺氧中毒的性别差异机制
- 批准号:
10577223 - 财政年份:2019
- 资助金额:
$ 41.37万 - 项目类别:
Mechanisms of sex differences in neonatal pulmonary oxygen toxicity
新生儿肺氧中毒的性别差异机制
- 批准号:
10641771 - 财政年份:2019
- 资助金额:
$ 41.37万 - 项目类别:
Mechanisms of sex specific differences in neonatal hyperoxic lung injury
新生儿高氧性肺损伤的性别差异机制
- 批准号:
9052817 - 财政年份:2015
- 资助金额:
$ 41.37万 - 项目类别:
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