Mechanisms of sex differences in neonatal pulmonary oxygen toxicity

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。 对早产儿的影响。出生后暴露于高浓度的 氧气(高氧)有助于BPD的发展。早产男婴 患BPD的风险更大。性二型的潜在原因 早产儿的结局尚不清楚。婴幼儿肺血管发育 暴露在高氧中的新生小鼠在雌性中保存得更好。我们的预赛 对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进行调节。具有启发性的是， 这些差异调控的血管生成转录本中有许多含有种子序列 对于促血管生成的miRNA，miR-30a，在其3‘非编码区。MiRNAs在生物信息学中的作用 在BPD中调停性别偏见的研究还很少。与此相关的是，女性的肺脏增加了 早期高氧暴露后miR-30a的表达。令人信服的是，我们的 初步数据显示，新生儿高氧性肺损伤的保护作用在 雌性miR30a-/-小鼠。缺氧诱导因子-1α增加miR-30a的表达 在出生后肺发育中的作用，特别是在高氧性损伤的恢复中。缺氧诱导因子-1α 在高氧暴露后的女性肺中，与其目标基因的结合更强。MIR-30a 下调Delta样配体4(DLL4)，它编码Notch家族的配体 感受器。DLL4/Notch活性增加，而封锁增强 新生血管的萌发和分枝。降低miR-30a水平，增加DLL4和 在人类BPD患者的肺中可以看到缺口的表达。我们假设更高的 通过缺氧诱导因子-1α表达MIR-30a通过以下方式保护肺血管发育 女性DLL4-Notch信号的下调。上述假设将得到检验。 通过以下具体目标：目标1：确定miR-30a在新生儿中的作用 高氧暴露后肺血管生成。目标2：定义特定性别 缺氧诱导因子-1α调控miR-30a基因转录的机制 死于新生儿高氧性肺损伤。目的3：确定内皮细胞DLL4的影响 MiR-30a对高氧暴露新生儿肺的抑制作用。这项提议将 解决支气管肺性分化发病率背后的知识差距 并为未来针对性别的治疗策略奠定了基础。

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.