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: 10578175
• 负责人: Krithika Lingappan
• 金额: $ 41.37万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10578175
• 关键词: 3' Untranslated Regions; Address; Alveolar; Attenuated; Automobile Driving; Bioinformatics; Biometry; Blood Vessels; Bronchopulmonary Dysplasia; Cell Surface Receptors; Cells; Chronic; Clinical; Data; Development; Developmental Biology; Down-Regulation; Endothelial Cells; Endothelium; Exposure to; Family; Female; Fibrosis; Foundations; Future; Genetic Transcription; Human; Hyperoxia; Impairment; In Vitro; Incidence; Knowledge; Laboratories; Ligands; Lung; Lung diseases; Mediating; Mesenchymal; Messenger RNA; MicroRNAs; Molecular; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Neonatal; Neonatal Hyperoxic Injury; Neonatology; Newborn Infant; Oxygen; Pathogenesis; Pathologic; Pathway interactions; Phenotype; Physicians; Physiological; Premature Infant; Pulmonary Fibrosis; Pulmonary Hypertension; Pulmonary Pathology; Recovery; Reporter; Risk; Role; Scientist; Seeds; Sex Differences; Signal Transduction; Testing; Transcript; Vascularization; angiogenesis; cost; crosslinking and immunoprecipitation sequencing; defined contribution; improved; in vivo; injury and repair; lung development; lung injury; male; mouse genetics; mouse model; multiple omics; neonatal human; neonatal mice; neonate; notch protein; novel; overexpression; postnatal; pre-clinical; premature; premature lungs; preservation; preterm newborn; prevent; pulmonary function; pulmonary vascular disorder; repaired; sex; sexual dimorphism; therapeutic target; transcriptome; treatment strategy

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.

支气管肺发育不良（BPD）是一种使人衰弱的肺部疾病， 是早产儿发病的最常见原因之一， 新生儿。出生后暴露于高浓度的氧气（高氧）有助于 对于BPD的发展。尽管在性别方面存在明确的性别差异， 男性中BPD和肺功能受损的发生率，分子机制 这背后的原因并不完全清楚。我们的实验室一直专注于 新生儿高氧性肺损伤性别差异的研究内皮至 间充质转化（EndoMT）有助于病理性 肺纤维化，但内皮MT在BPD中的作用尚未确定。重要的是， 我们发现，新生雌性小鼠的促纤维化蛋白表达降低， 标志物和改善肺泡化和肺血管发育相比， 在BPD的小鼠模型中与它们的雄性同窝出生仔进行比较。此外，我们还显示了临床前 和BPD中Endo-MT的临床证据。肺转录组分析 确定了抗纤维化的miRNA，miR-30a，作为驱动这些性- 具体差异。令人信服的是，女性在肺泡化和 miR30a-/-小鼠的血管发育丧失， 人类BPD肺。miR30 a抑制转录调节因子Snai1，以及 Dll4（其编码Notch配体）。Snai1和Dll4/Notch通路的激活 通过EndoMT促进纤维化我们假设在高氧女性新生儿中， miR30 a通过下调减弱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 通过以下具体目的进行测试：目的1：定义EndoMT和miR-1的贡献。 新生儿高氧性肺损伤30a。目的2：确定miR-30 a是否抑制EndoMT 和BPD在女性中通过抑制内皮Dll4-Notch信号传导。目标3：确定是否 miR-30a介导的内皮Snail 1抑制影响高氧诱导的 BPD中的EndoMT。该提案将解决分子生物学领域的知识差距， 支气管肺发育不良的性别差异发病率背后的机制， 为未来的性别特异性治疗策略奠定基础。