Genes contributing to patent ductus arteriosus susceptibility in preterm newborns

描述（由申请人提供）：足月婴儿，动脉导管收缩和管腔闭塞将肺循环和体循环分开。与足月婴儿相比，早产儿在出生后经常不能关闭动脉导管。持续的导管通畅导致肠系膜、肾脏和脑血流改变，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名早产儿因有症状的持续性动脉导管未闭（PDA）而接受治疗。在本提案中，我们将把我们之前的工作（在小鼠、绵羊和狒狒中进行的）扩展到人类导管，并确定可能发展为持久性PDA的早产儿人类导管中发生改变的分子途径。尽管在其他物种中已经发现了许多调节导管张力的基因和途径，但它们在促进或防止早产儿导管关闭方面的相对作用在很大程度上仍然未知。它们的重要性似乎取决于婴儿的成熟程度以及环境和遗传风险因素。在我们的应用中提出的实验利用一种新的方法来鉴定在导管关闭中起重要作用的导管基因，特别是在早产儿中。我们的研究小组最近发现了几个环境和遗传（多态性）风险因素，这些因素与早产儿PDA的持久性密切相关。我们计划确定当多态性危险因素（与PDA发病率增加相关）存在时，人类导管基因表达的变化。我们假设受风险因素影响的基因可能在早期发育阶段的导管闭合中发挥作用，因为多态性风险因素仅与早产儿（非足月婴儿）的持续性PDA相关。我们的具体目标是：1)确定一组与早产儿导管持续通畅相关的多态性风险因素；2)利用这些多态性风险因素，确定导管中的“易感性”基因（定义为在风险因素存在下表达改变的基因）；3)评估易感性基因表达改变对导管收缩性和其他下游基因的功能影响。总之，我们将使用多态性风险因素作为一种手段，发现有效的早产儿导管关闭所必需的分子途径。

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.