Genes contributing to patent ductus arteriosus susceptibility in preterm newborns

描述(申请人提供)：在足月儿，动脉导管的收缩和管腔的闭塞分离了肺和体循环。与足月儿相比，早产儿出生后经常不能关闭动脉导管。持续性导管通畅导致肠系膜、肾和脑血流改变，损害肺力学，增加肺水肿和出血的风险，并延长早产儿机械通气的需要。在美国，每年大约有25,000名早产儿接受有症状的持续性动脉导管未闭(PDA)的治疗。在这项提案中，我们将把我们之前的工作(在小鼠、绵羊和狒狒身上进行)扩展到人类导管，并确定在早产儿的人类导管中可能发生永久性PDA的分子通路。尽管许多调节导管张力的基因和途径已经在其他物种中被发现，但它们在促进或防止早产儿导管关闭方面的相对贡献仍然很大程度上尚不清楚。它们的重要性似乎取决于婴儿的成熟以及环境和遗传风险因素。在我们的申请中提出的实验利用一种新的方法来识别在导管关闭，特别是在早产儿中起关键作用的导管基因。我们小组最近发现了几个与早产儿PDA持久性密切相关的环境和遗传(多态)危险因素。我们计划确定当存在多态危险因素(与PDA发病率增加相关)时，人类导管基因表达的变化。我们推测，受危险因素影响的基因可能在导管闭合中发挥作用，这在早期发育阶段特别重要，因为多态危险因素只与早产儿(不是足月儿)持续性PDA有关。我们的具体目标是1)确定一组与早产婴儿持续性导管开放相关的多态危险因素，2)使用这些多态危险因素，识别导管中的“易感性”基因(定义为在危险因素存在时其表达发生变化的基因)，以及3)评估“易感性”基因表达改变对导管收缩和其他下游基因的功能影响。综上所述，我们将使用多态危险因素作为发现分子通路的一种手段，这些分子通路对于早产儿有效的导管关闭是必不可少的。

DESCRIPTION (provided by applicant): In full term infants, constriction of the ductus arteriosus and obliteration of its lumen separates the pulmonary and systemic circulations. In contrast with full term infants, preterm infants frequently fail to close their ductus arteriosus after birth. Persistent ductus patency causes altered mesenteric, renal and cerebral blood flows, impairs pulmonary mechanics, increases the risk of pulmonary edema and hemorrhage, and prolongs the need for mechanical ventilation in preterm infants. Each year, approximately 25,000 premature newborns are treated for a symptomatic, persistent patent ductus arteriosus (PDA) in the United States. In this proposal, we will extend our previous work (performed in mice, sheep, and baboons) to the human ductus and identify molecular pathways that are altered in premature human ductus that are likely to develop a persistent PDA. Although many of the genes and pathways that regulate ductus tone have been identified in other species, their relative contribution to promoting or preventing ductus closure in premature human infants remains largely unknown. Their importance appears to depend on the maturation of the infant as well as on environmental and genetic risk factors. The experiments proposed in our application utilize a novel approach to identify ductus genes that play an essential role in ductus closure particularly in preterm infants. Our group has recently identified several environmental and genetic (polymorphism) risk factors that are strongly associated with the persistence of a PDA in preterm infants. We plan to identify the changes in human ductus gene expression that occur when polymorphism risk factors (associated with an increased incidence of PDA) are present. We hypothesize that the genes that are affected by the presence of the risk factors may play a role in ductus closure that is particularly important at an early developmental stage since the polymorphism risk factors are only associated with a persistent PDA in preterm infants (not in full term infants). Our specific aims are 1) to identify a set of polymorphism risk factors that are associated with persistent ductus patency when infants are born prematurely, 2) to use these polymorphism risk factors, to identify "vulnerability" genes in the ductus (defined as genes whose expression are altered in the presence of the risk factors), and 3) to evaluate the functional effects of altered expressions of the "vulnerability" genes on ductus contractility and other downstream genes. In summary, we will use the polymorphism risk factors as a means of discovering molecular pathways that are essential for effective ductus closure in preterm infants.