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.
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.
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