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.

Public Health Relevance

The ultimate goal of this project is to identify molecular targets that can be used for the development of therapeutic agents to close the ductus arteriosus in premature infants. In addition, these studies will be the largest attempt to date to identify new genetic risk factors with which algorithms can be built to enable a more targeted use of current therapies. This project should bring us closer to our goal of using individual genetic and environmental risk factors (rather than institutional practices) to base our future PDA management.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Lin, Sara
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Shelton, Elaine L; Waleh, Nahid; Plosa, Erin J et al. (2018) Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data. Pediatr Res 84:458-465
Yarboro, Michael T; Durbin, Matthew D; Herington, Jennifer L et al. (2018) Transcriptional profiling of the ductus arteriosus: Comparison of rodent microarrays and human RNA sequencing. Semin Perinatol 42:212-220
Reese, Jeff; Shelton, Elaine L; Slaughter, James C et al. (2017) Prophylactic Indomethacin Revisited. J Pediatr 186:11-14.e1
Liebowitz, Melissa; Clyman, Ronald I (2017) Prophylactic Indomethacin Compared with Delayed Conservative Management of the Patent Ductus Arteriosus in Extremely Preterm Infants: Effects on Neonatal Outcomes. J Pediatr 187:119-126.e1
Liebowitz, Melissa; Koo, Jane; Wickremasinghe, Andrea et al. (2017) Effects of Prophylactic Indomethacin on Vasopressor-Dependent Hypotension in Extremely Preterm Infants. J Pediatr 182:21-27.e2
Smith, Caitlin J; Ryckman, Kelli K; Bahr, Timothy M et al. (2017) Polymorphisms in CYP2C9 are associated with response to indomethacin among neonates with patent ductus arteriosus. Pediatr Res 82:776-780
Clyman, Ronald I; Liebowitz, Melissa (2017) Treatment and Nontreatment of the Patent Ductus Arteriosus: Identifying Their Roles in Neonatal Morbidity. J Pediatr 189:13-17
Goyal, Ravi; Goyal, Dipali; Longo, Lawrence D et al. (2016) Microarray gene expression analysis in ovine ductus arteriosus during fetal development and birth transition. Pediatr Res 80:610-8
Liebowitz, Melissa; Clyman, Ronald I (2016) Antenatal Betamethasone: A Prolonged Time Interval from Administration to Delivery Is Associated with an Increased Incidence of Severe Intraventricular Hemorrhage in Infants Born before 28 Weeks Gestation. J Pediatr 177:114-120.e1
Patel, Priti M; Momany, Allison M; Schaa, Kendra L et al. (2016) Genetic Modifiers of Patent Ductus Arteriosus in Term Infants. J Pediatr 176:57-61.e1

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