REGULATION OF THE DUCTUS ARTERIOSUS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在早产儿中，动脉导管在分娩后经常保持开放许多天或数周。 在妊娠28周之前分娩的新生儿中，多达70%需要某种形式的治疗来关闭其患者导管。 如果不关闭，持续性动脉导管未闭与显著的发病率相关：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，动脉导管早期关闭可降低支气管肺发育不良的严重程度，并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，在使用它们的早产儿中诱导85%的导管闭合，但在20-30%的治疗婴儿中导管重新开放。最近的研究表明，导管壁缺氧的出生后发展是导致永久性关闭的解剖学重塑（管腔内皮细胞增殖、迁移和平滑肌细胞死亡）的重要步骤。 本申请中提出的研究将检查足月新生儿中早期自发性导管闭合所涉及的机制，以及持续性动脉导管未闭的早产狒狒模型延迟闭合所涉及的机制，该模型是模拟早产儿中导管通畅周围长期事件的唯一模型。 他们将研究改变导管张力的血管活性因子（例如，肾上腺素，一氧化氮）也与解剖重塑中涉及的生长因子和死亡因子的失调相互作用。 他们将研究早产新生儿导管壁缺氧增加的机制。 他们将使用免疫组织化学，Western和北方技术来研究mRNA和蛋白质表达的变化;他们将使用细胞迁移，增殖和细胞死亡的测定在离体血管，内皮细胞和平滑肌细胞培养。 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是什么启动和维持导管闭合过程以及为什么它不会发生在早产儿中的理解。

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.