Neuropeptides and chronic lung disease in newborns

神经肽与新生儿慢性肺病

• 批准号: 6655325
• 负责人: Mary E. Sunday
• 金额: $ 27.86万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655325
• 关键词: biomarker; blocking antibody; bombesin like peptide; bronchopulmonary dysplasia; chemoprevention; disease /disorder model; human tissue; hyperoxia; immunotherapy; laboratory mouse; model design /development; neuropeptide receptor; newborn animals; newborn human (0-6 weeks); nonhuman therapy evaluation

(Applicant's Abstract) The overall hypothesis is that bombesin-like peptide (BLP) is an early mediator of lung injury in bronchopulmonary dysplasia (BPD). Human infants with BPD have increased numbers of pulmonary neuroendocrine cells (PNECs) containing BLP. Elevated BLP could mediate lung injury in BPD, including interstitial fibrosis and reactive airways disease. The new data indicate that premature infants with elevated urine BLP levels at days 2-5 of age have a 10-fold increased risk of BPD, even when normalized for all other variables including prematurity. Elevated urine BLP levels also occur shortly after birth in 2 baboon models of BPD, in which BLP levels correlate with severity of subsequent chronic lung disease (CLD). Postnatal therapy with anti-BLP monoclonal antibody 2A11 protects against BPD in both models. The investigators propose to address the overall hypothesis using three Specific Aims. In Aims #1 and #2, they will test the hypotheses that hyperoxic newborn mice provide a valid model of CLD with similarity to specific features of human BPD. The investigators will determine how BLP contributes to lung injury in the murine model, and whether intratracheal BLP triggers specific pro-inflammatory cascades that also characterize hyperoxic CLD. The investigators will characterize histopathological changes over time, analyzing PNECs, mast cells, eosinophils, fibrosis, and alveolarization, and the kinetics of urine BLP and serum tryptase levels. They will assess BLP blocking antibody (2A11) as a prophylactic agent for CLD in the mouse model and evaluate which BLP receptors might be involved in mediating hyperoxic CLD using mice deficient in GRP-R, BRS-3, and/or NMB-R. In Aim #3, they will explore the role of BLP as a mediator of CLD in collaboration with other SCOR investigators. The investigators will analyze clinical factors associated with elevated urine BLP in premature infants, and estimate relative numbers of mast cells and eosinophils as compared to BLP levels in human infants with CLD. Finally, they will compare the course of hyperoxic CLD in genetically altered newborn mice with over-expression and/or deficiency of heme oxygenase-1, CRH, syndecans, or a panel of pro-inflammatory molecules including CCR3, CXCR3, NK-1R, and CDl0/NEP 24.11. These studies will help to clarify cellular and molecular mechanisms by which BLP could contribute to the pathophysiology of BPD, and facilitate the development of novel prophylactic treatments for infants at risk.

（申请人的摘要）总体假设是bombesin样肽 （BLP）是支气管肺发育不良（BPD）中肺损伤的早期介体。 BPD的人类婴儿的肺神经内分泌数量增加 包含BLP的细胞（PNEC）。升高的BLP可以介导BPD中的肺损伤， 包括间质纤维化和反应性气道疾病。新数据 表明在第2-5天的尿液BLP水平升高的早产婴儿 年龄的BPD风险增加了10倍，即使对所有其他人进行标准化 变量包括早产。尿液BLP水平升高也很快发生 出生后，BPD的2个狒狒模型，其中BLP水平与 随后的慢性肺病（CLD）的严重程度。产后治疗 抗BLP单克隆抗体2A11在这两种模型中都可以防止BPD。这 研究人员建议使用三个特定的特定假设解决总体假设 目标。在目标＃1和＃2中，他们将测试过多氧化新生儿的假设 小鼠提供了有效的CLD模型，该模型与特定特征相似 人BPD。调查人员将确定BLP如何促进肺损伤 在鼠模型中以及气管内BLP是否触发特定 促炎性级联反应也表征了高氧化物CLD。这 研究人员将随着时间的流逝表征组织病理学变化，分析 PNEC，肥大细胞，嗜酸性粒细胞，纤维化和肺泡化，以及 尿液BLP和血清胰蛋白酶水平的动力学。他们将评估BLP阻塞 抗体（2A11）作为小鼠模型中CLD的预防剂，并且 评估哪些BLP受体可能参与介导高氧化物CLD 使用缺乏GRP-R，BRS-3和/或NMB-R的小鼠。在AIM＃3中，他们将 探索BLP作为CLD的调解人与其他SCOR合作的作用 调查人员。研究人员将分析与 早产婴儿的尿液BLP升高，并估计桅杆的相对数量 与患有CLD的人类婴儿的BLP水平相比，细胞和嗜酸性粒细胞。 最后，他们将比较遗传改变的高氧化物CLD的过程 血红素氧酶-1，CRH，过表达和/或缺乏的新生小鼠，CRH， Syndecans或一组促炎分子，包括CCR3，CXCR3， NK-1R和CDL0/NEP 24.11。这些研究将有助于阐明细胞和 BLP可以有助于有助于的分子机制 BPD，并促进开发新的预防治疗 有风险的婴儿。