Mechanisms of sex differences in neonatal pulmonary oxygen toxicity

支气管肺发育不良（BPD）是一种使人衰弱的肺部疾病， 早产儿的后果。出生后接触高浓度的 氧气（高氧）有助于BPD的发展。早产男婴 患上BPD的风险更大两性异形的原因 早产儿的结局尚不清楚。肺血管发育 暴露于高氧的新生小鼠在雌性中保存得更好。我们的初步 肺转录组的分析表明，血管生成是不同的， 在高氧暴露的新生雄性和雌性小鼠之间调节。建议， 这些差异调节的血管生成转录物中有许多含有种子序列， 对于促血管生成的miRNA，miR-30 a，在其3' UTR内。miRNAs在 BPD中的中介性别偏见研究不足。与此相关的是，女性的肺部 早期暴露于高氧后的miR-30 a表达。令人信服的是，我们 初步数据表明，对新生儿高氧肺损伤的保护作用丧失， 雌性miR 30 a-/-小鼠。HIF-1α增加miR-30 a表达，并在调节miR-30 a表达中起重要作用。 在出生后肺发育中的作用，特别是在高氧损伤的恢复中。HIF-1α 在高氧暴露后，女性肺部与其靶基因的结合更强。miR-30a 下调Delta样配体4（Dll 4），其编码Notch家族的配体， 受体。增加的DLL 4/Notch活性降低，而阻断增强 血管生成发芽和分枝。miR-30 a水平降低，D114和D115水平升高， Notch表达见于人BPD患者肺中。我们假设， miR-30 a通过HIF-1α表达保护肺血管发育 在雌性中下调Dll 4-Notch信号传导。将对上述假设进行检验 目的1：确定miR-30 a在新生儿中的作用， 高氧暴露后的肺血管生成。目标2：定义性别特异性 恢复期HIF-1α调控miR-30 a转录的机制 新生儿高氧肺损伤目的3：确定内皮DLL 4的影响 在暴露于高氧的新生儿肺中miR-30 a的抑制。这项建议会 解决支气管肺结核性别差异发病率背后的知识差距 并为未来的性别特异性治疗策略奠定基础。

Bronchopulmonary dysplasia (BPD) is a debilitating lung disease with long-term consequences in premature neonates. Postnatal exposure to high concentrations of oxygen (hyperoxia) contributes to the development of BPD. Premature male neonates are at a greater risk of developing BPD. The reasons underlying sexually dimorphic outcomes in premature neonates are not known. Pulmonary vascular development in neonatal mice exposed to hyperoxia is better preserved in females. Our preliminary analysis of the pulmonary transcriptome demonstrates that angiogenesis is differentially modulated between hyperoxia-exposed neonatal male and female mice. Suggestively, many of these differentially regulated angiogenic transcripts contained a seed sequence for the pro-angiogenic miRNA, miR-30a, within their 3’ UTR. The role of miRNAs in mediating sex biases in BPD is understudied. Relatedly, female lungs had increased miR-30a expression following early exposure to hyperoxia. Compellingly, our preliminary data indicate that protection from neonatal hyperoxic lung injury is lost in female miR30a-/- mice. Hif-1α increases miR-30a expression and plays an important role in post-natal lung development, especially in recovery from hyperoxic injury. HIF-1α binding to its target genes is greater in female lungs after hyperoxia exposure. miR-30a downregulates Delta like ligand 4 (Dll4), which encodes a ligand for the Notch family of receptors. Increased DLL4/Notch activity decreases, while blockade enhances angiogenic sprouting and branching. Decreased miR-30a levels and increased Dll4 and Notch expression are seen in human BPD patient lungs. We hypothesize that higher miR-30a expression through HIF-1α preserves lung vascular development by downregulation of Dll4-Notch signaling in females. The above hypothesis will be tested by the following specific aims: Aim 1: Establish the role of miR-30a in neonatal pulmonary angiogenesis after hyperoxia exposure. Aim 2: Define the sex-specific mechanisms governing transcriptional regulation of miR-30a by HIF-1α during recovery from neonatal hyperoxic lung injury. Aim 3: Determine the impact of endothelial DLL4 suppression by miR-30a in the neonatal lung exposed to hyperoxia. This proposal will address knowledge gaps behind the sexual divergent incidence of bronchopulmonary dysplasia and lay the foundation for future sex-specific treatment strategies.