Mechanistic Roles of Adrenomedullin and its Signaling Receptors in Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension

肾上腺髓质素及其信号受体在实验性支气管肺发育不良和肺动脉高压中的机制作用

• 批准号: 9767851
• 负责人: Binoy Shivanna
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767851
• 关键词: Address; Air; Alveolar; Animals; Area; Autopsy; Biological Markers; Blood Vessels; Bronchopulmonary Dysplasia; Cell Death; Cell Survival; Cell physiology; Cells; Chronic lung disease; Clinical Trials; Congenital diaphragmatic hernia; Data; Development; Disease; Endothelial Cells; Endothelium; Environment; Exposure to; Extracellular Signal Regulated Kinases; Female; Functional disorder; Generations; Genes; Goals; Harvest; Heart Function Tests; Human; Hyperoxia; In Vitro; Infant; Infant Development; Inflammation; Injury; Institutes; Interruption; Knock-out; Knowledge; Lead; Lung; MAPK3 gene; Messenger RNA; Mitogen-Activated Protein Kinases; Molecular; Morbidity - disease rate; Mus; NOS3 gene; Neonatal; Nitric Oxide; Nitric Oxide Donors; Pathogenesis; Pathogenicity; Patients; Peptide Signal Sequences; Peptides; Premature Infant; Process; Proteins; Pulmonary Hypertension; Receptor Signaling; Research; Resources; Respiratory physiology; Rodent; Role; Sampling; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; Testing; Tissue Sample; Transgenic Mice; Vascular Diseases; Vascular remodeling; adrenomedullin; adrenomedullin receptor; angiogenesis; base; calcitonin receptor-like receptor; clinically significant; design; effective therapy; fetal; human disease; improved; injury and repair; innovation; intervention effect; lung development; lung injury; male; mortality; mouse model; neonatal lung injury; novel; overexpression; oxygen toxicity; prevent; pulmonary artery endothelial cell; receptor; receptor-activity-modifying protein; therapeutic target; therapy development; translational approach

Abstract/Summary Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of preterm infants; development of pulmonary hypertension (PH) in these infants increases BPD-associated mortality and morbidity. Interrupted angiogenesis and alveolarization, endothelial cell dysfunction, and pulmonary vascular remodeling contribute to the pathogenesis of BPD and PH, a disease for which there are no specific therapies. Adrenomedullin (AM) is an endogenous peptide that regulates angiogenesis and endothelial cell survival and function, making this peptide an ideal target to develop therapies for this disease. AM signals through its cognate receptors, calcitonin-receptor like receptor (Calcrl) and receptor activity-modifying protein (RAMP)-2. Recent studies indicate that AM signaling is necessary for lung development and to ameliorate lung injury in neonatal rodents. However, it is unclear if AM improves BPD-associated lung and pulmonary vascular dysfunction in these animals. Further, the cellular and molecular mechanisms by which AM signaling protects against neonatal lung injury are unknown. So, we propose to address these knowledge gaps using an established neonatal mouse model of hyperoxic lung injury. Our preliminary studies indicate that AM signaling is necessary for healthy lung development and to mitigate hyperoxia-induced lung injury in neonatal mice. Further, we observed that AM regulates extracellular signal-regulated kinase (ERK) 1/2 activation and endothelial nitric oxide synthase (eNOS) expression in the lungs of neonatal mice and in fetal human pulmonary endothelial cells. Based on these data, we will test the central hypothesis that endothelial-specific AM signaling activates ERK 1/2 and eNOS to promote angiogenesis and prevent endothelial cell dysfunction in neonatal lungs, which in turn will mitigate hyperoxia-induced experimental BPD and PH. We will use a unique combination of molecular, cellular, functional, and translational approaches to test this hypothesis. In Aim 1, we will use transgenic mice to determine if endothelial-specific AM signaling is necessary and sufficient to protect neonatal mice against hyperoxia-induced lung and pulmonary vascular injury and dysfunction. In Aim 2, we will use double transgenic mice to examine the interactions between AM, ERK 1/2 signaling, and eNOS activity in the developing lungs exposed to hyperoxia. Aim 3, which has two sub-aims, is designed to examine the translational potential of our proposal. In sub-aim 1, we will examine if AM signaling regulates hyperoxia-induced injury in human pulmonary endothelial cells. In sub-aim 2, we will determine the expression of AM and its receptors in the lungs of infants with and without BPD. We expect that successful completion of these studies would provide a mechanistic rationale for targeting AM, Calcrl, or RAMP2 to develop meaningful therapies for BPD and PH. Further, these studies could provide a scientific premise for clinical trials with AM to treat BPD patients with PH. Our studies could also positively impact other angiogenesis- and PH-related research areas, such as congenital diaphragmatic hernia and congenital lung hypoplasia.

摘要/摘要 支气管肺发育不良（BPD）是早产儿最常见的慢性肺部疾病。发展 这些婴儿中肺动脉高压（pH）的增加会增加与BPD相关的死亡率和发病率。中断 血管生成和肺泡化，内皮细胞功能障碍和肺血管重塑有助于 对于BPD和pH的发病机理，这种疾病没有特定的疗法。肾上腺果蛋白（AM） 是一种调节血管生成和内皮细胞存活和功能的内源性肽 肽是开发该疾病疗法的理想靶标。通过其同源受体信号， 降钙素受体（例如受体（CALCRL）和受体活性改良蛋白（RAMP）-2）-2。最近的研究 表明AM信号传导对于肺发育和改善新生儿啮齿动物的肺损伤是必需的。 但是，目前尚不清楚AM是否改善了BPD相关的肺和肺血管功能障碍 动物。此外，AM信号传导可预防新生儿肺的细胞和分子机制 伤害未知。因此，我们建议使用已建立的新生小鼠解决这些知识差距 高氧肺损伤的模型。我们的初步研究表明，AM信号传导对于健康的肺部是必需的 发育并减轻新生小鼠高氧诱导的肺损伤。此外，我们观察到AM 调节细胞外信号调节激酶（ERK）1/2激活和内皮一氧化氮合酶 （eNOS）在新生小鼠和胎儿人肺内皮细胞中的表达。基于 这些数据，我们将测试中心假设，即内皮特异性AM信号传导激活ERK 1/2和 eNOS促进血管生成并预防新生儿肺部内皮细胞功能障碍 减轻高氧诱导的实验BPD和pH。我们将使用分子，细胞的独特组合 功能性和转化方法来检验该假设。在AIM 1中，我们将使用转基因小鼠 确定内皮特异性的AM信号是否需要且足以保护新生小鼠免受 高氧引起的肺和肺血管损伤和功能障碍。在AIM 2中，我们将使用双重转基因 小鼠检查AM，ERK 1/2信号传导和发育中的eNOS活性之间的相互作用 暴露于高氧。 AIM 3具有两个子AIM，旨在检查我们的翻译潜力 提议。在Sub-Aim 1中，我们将检查AM信号是否调节人肺部高氧诱导的损伤 内皮细胞。在Sub-Aim 2中，我们将确定AM及其受体在婴儿肺中的表达 有和没有BPD。我们预计这些研究的成功完成将提供机械 针对AM，CALCRL或RAMP2的靶向理由，以开发BPD和pH的有意义的疗法。此外，这些 研究可以为与AM的临床试验提供科学前提，以治疗pH值的BPD患者。我们的研究 还可以积极影响其他血管生成和pH相关的研究领域，例如先天性 diaphragmania疝气和先天性肺发育不全。