Sex as biological variable in Bronchopulmonary Dysplasia: Role of the Notch pathway

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异常凹槽 信号在许多慢性肺部疾病和Notch的发病机制中的作用 在患有BPD的婴儿的肺中可以看到激活。异常切迹的作用 BPD患者肺血管生成障碍的信号转导机制尚未确定。关键是， 新生雌性小鼠的肺泡化和肺血管得到改善 发育，这与Notch通路激活和减少有关 Notch配体DLL4在Wistar小鼠模型中的表达 每桶。这一创新提案的总体目标是定义性别特定的角色 Notch通路激活在调节新生儿肺血管生成中的作用 高氧性肺损伤。我们推测，减少Notch的激活是继发性的 小分子DLL4的表达保护了女婴的肺血管生成。这个 上述假设将通过以下具体目标进行检验：目标1：阐明 内皮细胞DLL4(Notch配体)在肺调节中的时空作用 血管生成。目的2：确定肺内皮细胞Notch信号转导通路在肺损伤中的作用 高氧暴露对发育中肺血管生成的调节作用。这 该提案将解决性行为背后的分子机制方面的知识空白 支气管肺发育不良的不同发病情况及为未来奠定基础 针对性别的治疗策略。

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. Aberrant Notch signaling contributes to the pathogenesis of many chronic lung diseases and Notch activation is seen in lungs of human infants with BPD. The role of aberrant Notch signaling in pulmonary dysangiogenesis in BPD has not been determined. Critically, neonatal female mice have improved alveolarization and pulmonary vascular development, which is associated with, decreased Notch pathway activation and expression of the Notch ligand Dll4 compared to male littermates in a murine model of BPD. The overall aim of this innovative proposal is to define the role of sex-specific activation of Notch pathway in modulating pulmonary angiogenesis in neonatal hyperoxic lung injury. We hypothesize that decreased Notch activation secondary to lesser Dll4 expression preserves pulmonary angiogenesis in female neonates . The above hypothesis will be tested by the following specific aims: Aim 1: Elucidate the spatio-temporal role of endothelial DLL4 (Notch ligand) in modulating pulmonary angiogenesis. Aim 2: Determine the role pulmonary endothelial Notch signaling in modulating pulmonary angiogenesis in the developing lung exposed to hyperoxia. 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.