NEUROPEPTIDES IN LUNG DEVELOPMENT AND INJURY

神经肽在肺发育和损伤中的作用

• 批准号: 7349771
• 负责人: Mary E. Sunday
• 金额: $ 2.94万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349771
• 关键词: NEUROPEPTIDES; LUNG; DEVELOPMENT; INJURY

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our overall hypothesis is that bombesin-like peptide (BLP) is an early mediator of lung injury in bronchopulmonary dysplasia (BPD). Increased numbers of pulmonary neuroendocrine cells (PNECs) containing BLP occur in human infants with BPD. Pulmonary BLP and BLP receptor mRNA levels normally peak during the canalicular period, declining to low levels during alveolarization. Excessive BLP in preterm infants could potentiate BPD, mediating peribrochiolar and interstitial fibrosis, reactive airways disease, and inhibiting alveolarization. We observe increased urine BLP levels approximately 48-72h after birth in 2 distinct baboon models of BPD, with BLP levels correlating with severity of subsequent chronic lung disease. Postnatal treatment with anti-BLP monoclonal antibody 2A11 protects against BPD in both models. We will address our overall hypothesis using three Aims: AIM 1: To determine the pharmacological mechanisms and clinical usefulness of 2A11 for preventing acute and chronic lung disease in preterm baboons in vivo. Hypothesis number 1: 2A11 functions by blocking pro-inflammatory effects of BLP during early BPD. We will also evaluate a BLP receptor antagonist. AIM 2: To analyze cellular and pharmacological mechanisms of BLP and 2A11 effects using simplified in vitro alveolarization systems. Hypotheses number 2: (a) Abnormally elevated BLP during the early saccular period inhibits alveolarization. (b) Key target cells for BLP during this process are mesenchymal cells, which alter production of mediators to become anti-angiogenic. We will characterize fibroblast-derived mRNAs included by BLP that are able to midulate alveolarization. AIM 3: To explore the role of BLP and/or PNECs as mediators of other BPD-associated changes, in collaboration with other U10 investigators. Hypothesis number 3: BLP is induced by oxidant injury and acts as proximal cytokine, promoting acute and chronic inflammation with interstitial fibrosis. Effective anti-oxidant therapy should decrease BLP secretion, leading to improved clinical outcomes. Combined modality treatment with anti-oxidants together with 2A11 will be considered as resources permit. These approaches will be instrumental in clarifying the underlying pathophysiology of BPD. The proposed investigations will facilitate rational improvement in therapeutics based on comprehensive understanding of disease mechanisms.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。我们的总体假设是，炸弹蛋白样肽（BLP）是支气管肺发育不良（BPD）中肺损伤的早期介体。在患有BPD的人类婴儿中，含有BLP的肺神经内分泌细胞（PNEC）数量增加。肺BLP和BLP受体mRNA水平通常在大口腔期间达到峰值，在肺泡化期间下降到低水平。早产儿过度的BLP可以增强BPD，介导细胞纤维化和间质纤维化，反应性气道疾病以及抑制肺泡化。我们观察到在2种不同的BPD模型中出生后约48-72h的尿液BLP水平升高，BLP水平与随后的慢性肺部疾病的严重程度相关。抗BLP单克隆抗体2A11的产后治疗在这两种模型中都可以预防BPD。我们将使用三个目的解决我们的总体假设：目标1：确定2A11的药理机制和临床实用性，以防止体内早产狒狒中急性和慢性肺部疾病。假设编号1：2A11通过阻止BPD早期BLP的促炎作用来发挥作用。我们还将评估BLP受体拮抗剂。目的2：使用简化的体外肺泡系统分析BLP和2A11效应的细胞和药理机制。假设2：（a）早期的寒冷时期抑制肺泡化的BLP异常升高。 （b）在此过程中，BLP的关键靶细胞是间充质细胞，它改变了介体的产生，成为抗血管生成。我们将表征BLP包含的成纤维细胞衍生的mRNA，这些mRNA能够中度肺泡化。 AIM 3：与其他U10研究人员合作，探索BLP和/或PNEC作为其他BPD相关变化的介体的作用。假设数字3：BLP是由氧化剂损伤引起的，并且起着近端细胞因子的作用，从而促进急性和慢性炎症，并用间质纤维化。有效的抗氧化剂疗法应减少BLP分泌，从而改善临床结果。将抗氧化剂与2A11一起使用的模态处理将被视为资源许可。这些方法将有助于阐明BPD的潜在病理生理。拟议的研究将基于对疾病机制的全面理解，促进治疗剂的合理改善。