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
• 负责人: Krithika Lingappan
• 金额: $ 53.22万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447105
• 关键词: 3' Untranslated Regions; Address; Alveolar; Binding; Biological Assay; Biomedical Engineering; Blood Vessels; Bronchopulmonary Dysplasia; Cells; Chronic; Data; Development; Disease; Down-Regulation; Endothelium; Exposure to; Family; Female; Foundations; Future; Genes; Genetic; Human; Hyperoxia; In Vitro; Incidence; Infant; Injury; Knowledge; Lead; Ligands; Luciferases; Lung; Lung diseases; Mediating; MicroRNAs; Molecular; Morbidity - disease rate; Mus; Neonatal; Newborn Infant; Outcome; Oxygen; Pathologic; Patients; Phenotype; Play; Publishing; Pulmonary Hypertension; Pulmonary Pathology; Recovery; Regulation; Reporter; Risk; Role; Seeds; Sex Bias; Sex Differences; Signal Transduction; Small RNA; Suggestion; Testing; Therapeutic; Transcript; Transcriptional Regulation; Vascularization; angiogenesis; base; care costs; chromatin immunoprecipitation; clinically relevant; experimental study; in vivo; knock-down; loss of function; lung development; lung injury; lung microvascular endothelial cells; lung preservation; male; mouse genetics; neonatal exposure; neonatal human; neonatal mice; neonate; new therapeutic target; notch protein; novel strategies; overexpression; oxygen toxicity; postnatal; premature; premature lungs; preservation; preterm newborn; pulmonary vascular disorder; receptor; repaired; sex; sexual dimorphism; transcriptome; treatment strategy

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.

支气管肺发育不良（BPD）是一种使人衰弱的肺部疾病，长期存在 早产儿的后果。产后接触高浓度 氧气（高氧）有助于 BPD 的发展。早产男性新生儿 患 BPD 的风险更大。两性异形的原因 早产儿的结果尚不清楚。肺血管发育 暴露于高氧环境的新生小鼠在雌性中保存得更好。我们的初步 肺转录组分析表明血管生成存在差异 在高氧暴露的新生雄性和雌性小鼠之间进行调节。暗示性地， 许多这些差异调节的血管生成转录物包含种子序列 对于促血管生成 miRNA，miR-30a，位于其 3' UTR 内。 miRNA 的作用 调节 BPD 中的性别偏见尚未得到充分研究。与此相关的是，女性的肺部增加了 早期暴露于高氧后 miR-30a 的表达。令人信服的是，我们的 初步数据表明，新生儿高氧性肺损伤的保护作用丧失 雌性 miR30a-/- 小鼠。 Hif-1α 增加 miR-30a 表达并发挥重要作用 在产后肺部发育中的作用，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 (Dll4)，该配体编码 Notch 家族的配体 受体。 DLL4/Notch 活性增加会降低，而封锁则会增强 血管生成发芽和分支。 miR-30a 水平降低，Dll4 和 Notch 表达见于人类 BPD 患者肺部。我们假设更高 通过 HIF-1α 表达 miR-30a 可通过以下方式保护肺血管发育： 女性中 Dll4-Notch 信号的下调。将检验上述假设 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 恢复过程中 HIF-1α 对 miR-30a 转录调控的机制 新生儿高氧性肺损伤。目标 3：确定内皮 DLL4 的影响 暴露于高氧的新生儿肺中 miR-30a 的抑制。该提案将 解决支气管肺疾病性别差异发病率背后的知识差距 发育不良，并为未来针对性别的治疗策略奠定基础。