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

性别作为支气管肺发育不良的生物学变量：Notch 通路的作用

• 批准号: 10578253
• 负责人: Krithika Lingappan
• 金额: $ 20.06万
• 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: 2020-06-23 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578253
• 关键词: Sex; biological; variable; Bronchopulmonary; Dysplasia

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.

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。尽管已经确定了性别特异性差异， 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异常刻缺蛋白 信号传导有助于许多慢性肺部疾病的发病机制， 在患有BPD的人类婴儿的肺中观察到活化。异常Notch的作用 BPD中肺血管生成障碍的信号传导尚未确定。重要的是， 新生雌性小鼠具有改善的肺泡形成和肺血管 发展，这与减少Notch途径激活和 与同窝出生的雄性小鼠相比，Notch配体Dll4在小鼠模型中的表达 波士顿警局这一创新提案的总体目标是界定性别歧视的作用， 激活Notch途径调节新生儿肺血管生成 高氧肺损伤我们假设继发于 较少的Dll4表达保留了雌性新生儿的肺血管生成。的 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）在调节肺动脉高压中时空作用 血管生成目的2：确定肺内皮Notch信号转导在肺动脉高压中的作用。 调节暴露于高氧的发育中的肺中的肺血管生成。这 这项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发病率趋异，为今后的研究奠定基础 针对性别的治疗策略。

项目成果

Does the Epigenome Hold Clues to Leptin-associated Hypertension in Obesity?

• DOI: 10.1165/rcmb.2021-0199ed
• 发表时间: 2021-08
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Lingappan K

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan.

生长分化因子15在肺部疾病和衰老中的作用：整个生命周期的潜在作用。

• DOI: 10.3389/fmed.2020.594137
• 发表时间: 2020
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Al-Mudares F;Reddick S;Ren J;Venkatesh A;Zhao C;Lingappan K
• 通讯作者: Lingappan K

Molecular insights using spatial transcriptomics of the distal lung in congenital diaphragmatic hernia.

使用先天性膈疝远端肺空间转录组学的分子见解。

• DOI: 10.1152/ajplung.00154.2023
• 发表时间: 2023
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Lingappan,Krithika;Olutoye2nd,OluyinkaO;Cantu,Abiud;CantuGutierrez,ManuelEliezer;Cortes-Santiago,Nahir;Hammond,JD;Gilley,Jamie;Quintero,JoselynRojas;Li,Hui;Polverino,Francesca;Gleghorn,JasonP;Keswani,SundeepG
• 通讯作者: Keswani,SundeepG