REGULATION OF THE DUCTUS ARTERIOSIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。早产儿的动脉导管经常在分娩后数天或数周内保持开放。在妊娠28周前出生的新生儿中，多达70%需要某种形式的治疗来关闭患者的导管。如果不闭合，持续的动脉导管未闭与显著的发病率相关：支气管肺发育不良（长时间需要机械通气）和坏死性小肠结肠炎。大量研究表明，早期关闭动脉导管可降低支气管肺发育不良的严重程度，降低坏死性小肠结肠炎的发生率。虽然前列腺素合成抑制剂，如吲哚美辛，在85%的早产儿中会导致导管关闭，但在20-30%的治疗婴儿中会发生导管重新打开。最近的研究表明，出生后的导管壁缺氧是解剖重构（管腔内皮细胞增殖、迁移和平滑肌细胞死亡）的重要步骤，最终导致永久性关闭。本申请中提出的研究将研究足月新生儿早期自发导管关闭的机制，以及持续动脉导管未闭的早产狒狒模型延迟关闭的机制，这是唯一一个模仿早产儿动脉导管开放周围长期事件的模型。他们将检验一种假设，即改变导管张力的血管活性因子（如前列腺素、一氧化氮）也与解剖重构中涉及的生长因子和死亡因子的失调相互作用。他们将研究增加早产儿导管壁缺氧的机制。他们将使用免疫组织化学、Western和Northern技术来研究mRNA和蛋白质表达的变化；他们将在分离的血管、内皮细胞和平滑肌细胞中进行细胞迁移、增殖和细胞死亡的测定。他们将描述受体群体的变化，并在体内测试他们的发现。这些研究应该增加我们对出生后启动和维持导管闭合过程的理解，以及为什么它不会发生在早产儿身上。

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. In the premature infant, the ductus arteriosus frequently remains open for many days or weeks after delivery. As many as 70% of newborns delivered prior to 28 weeks gestation will require some form of therapy to close their patient ductus. If left unclosed, a persistent patent ductus arteriosus is associated with significant morbidity: bronchopulmonary dysplasia (with its prolonged need for mechanical ventilation) and necrotizing enterocolitis. Numerous studies have shown that early closure of the ductus arteriosus decreases the severity of bronchopulmonary dysplasia and decreases the incidence of necrotizing enterocolitis. Although inhibitors of prostaglandin synthesis, like indomethacin, induce ductus closure in 85% of preterm infants in whom they are used, ductus reopening occurs in 20-30% of treated infants. Recent studies demonstrate that the postnatal development of ductus wall hypoxia is an essential step in the anatomic remodeling (luminal endothelial proliferation, migration, and smooth muscle cell death) that leads to permanent closure. The studies proposed in this application will examine the mechanisms involved in early, spontaneous ductus closure in the full-term newborn and those involved in the delayed closure of the premature baboon model of persistent patent ductus arteriosus, which is the only model that mimics the long-term events surrounding ductus patency in the preterm human. They will examine the hypothesis that vasoactive factors that alter ductus tone (e.g., prostaglandins, nitric oxide) also interact with an deregulate the growth factors and death factors involved in anatomic remodeling. They will examine mechanisms to increase ductus wall hypoxia in the preterm newborn. They will use immunohistochemical, Western, and Northern techniques to study changes in mRNA and protein expression; they will use assays of cell migration, proliferation, and cell death in isolated vessels, endothelial and smooth muscle cells in culture. They will characterize changes in receptor populations and test their findings in vivo. These studies should increase our understanding of what initiates and sustains the process of ductus closure after birth and why it does not occur in the preterm infant.