REGULATION OF THE DUCTUS ARTERIOSUS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在早产儿中，动脉导管经常在分娩后数天或数周内保持开放。多达70%的新生儿在怀孕28周前出生，需要某种形式的治疗来关闭他们的患者导管。如果不闭合，持续的动脉导管未闭与显著的发病率有关：支气管肺发育不良(长期需要机械通气)和坏死性小肠结肠炎。大量研究表明，早期闭合动脉导管可减轻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。尽管前列腺素合成的抑制剂，如消炎痛，在使用它们的早产儿中85%会导致导管关闭，但在接受治疗的婴儿中，有20%-30%的婴儿会发生导管重新开放。最近的研究表明，出生后导管管壁缺氧的发展是导致永久闭合的解剖重建(管腔内皮细胞增殖、迁移和平滑肌细胞死亡)的关键步骤。本申请中提出的研究将检验足月新生儿早期自发关闭导管的机制，以及那些涉及持续动脉导管未闭的早产儿模型延迟关闭的机制，该模型是唯一模拟早产儿动脉导管开放周围的长期事件的模型。他们将检验这样一种假设，即改变导管张力的血管活性因子(如前列腺素、一氧化氮)也与血管紧张素相互作用，从而使参与解剖重塑的生长因子和死亡因子失去调控。他们将研究早产儿增加管壁缺氧的机制。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；他们将使用细胞迁移、增殖和细胞死亡的分析方法，在培养中的分离血管、内皮细胞和平滑肌细胞。他们将描述受体种群的变化，并在体内测试他们的发现。这些研究应该会增加我们对出生后导管关闭的启动和维持过程以及为什么早产儿不会发生这一过程的理解。

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.