Genes contributing to patent ductus arteriosus susceptibility in preterm newborns

描述（由申请方提供）：在足月婴儿中，动脉导管收缩和管腔闭塞将肺循环和体循环分开。与足月儿相比，早产儿出生后常常不能闭合动脉导管。持续性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，并增加早产儿机械通气的需要。在美国，每年约有25，000名早产儿接受症状性持续性动脉导管未闭（PDA）治疗。 在这项提议中，我们将把我们以前的工作（在小鼠、绵羊和狒狒中进行）扩展到人类导管，并确定在可能发展为持续性PDA的早产人类导管中改变的分子通路。虽然许多调节导管张力的基因和途径已经在其他物种中被确定，但它们对促进或预防人类早产儿导管闭合的相对贡献仍然很大程度上未知。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。在我们的申请中提出的实验利用一种新的方法来鉴定在导管闭合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）的危险因素，这些因素与早产儿PDA的持续存在密切相关。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，受危险因素影响的基因可能在导管闭合中起作用，这在早期发育阶段特别重要，因为多态性危险因素仅与早产儿（而不是足月儿）的持续性PDA相关。我们的具体目标是：1）确定一组与早产儿持续性导管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“脆弱性”基因，（定义为在风险因素存在下表达改变的基因），和3）评估“易损性”基因的表达改变对导管收缩性和其他下游基因的功能影响。总之，我们将使用多态性危险因素作为发现早产儿有效导管闭合所必需的分子途径的一种手段。

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.