Grants and Contracts Details
The transition to pulmonary respiration at birth requires alteration of the cardiopulmonary circulation which includes the functional closure of an arterial shunt known as the ductus arteriosus (DA). We recently reported that the genetic or pharmacological activation cyclooxygenase-2 (COX-2) in neonatal mice results in the failure of DA closure after birth, a condition known as patent DA, which in humans is the second most common congenital heart disease. We also observed a high level of COX-2 expression in the DA of full-term neonatal mice by immunohistochemistry, suggesting that expression of COX-2 in the DA is important for normal closure after birth. In human infants, patent DA is primarily associated with premature births, although the mechanism(s) responsible for the increased incidence have not been determined. The proposed work will examine the effect of gestational age on the expression of the two COX isoforms in the DA of preterm and full-term neonatal mice and determine whether alterations in either isoform contribute to increased patent DA in preterm neonates. Real-time reverse transcriptase-polymerase chain reaction and Western blot analysis will be utilized to quantitate the expression of the COX isoforms. This will determine whether the DA of preterm neonates shows attenuated expression of COX-2. To determine whether this reduced expression of COX-2 correlates with increased patent DA, neonatal mice at preterm gestation will be examined and DA closure will be quantitated by histological morphometric analysis. In contrast to vasoconstrictor prostanoids, prostaglandin (PG) E2 is known to be a potent inhibitor of DA closure. To determine whether COX-1 is the isoform primarily responsible for synthesizing PGE2 which dilates the DA, PGE2 levels in the plasma and DA of COX-1-deficient and COX-2-deficient mice will be measured by radio-immuno assay and compared with levels in wild-type mice. PGE21eveis in the plasma and DA will be compared between preterm and full-term neonates to determine whether a higher level of COX-1-derived PGE2 in preterm neonates contributes to reduced DA closure. We will use genetic and pharmacological inactivation of COX-2 in mice as models of patent DA to determine the efficacy of a COX-1-specific inhibitor to reduce dilatory PGE2, thereby facilitating postnatal DA closure. . 11. Amount Requested: $65,000 Year 1 $65,000 Year2 $65,000 Year 3 $65,000 Year 4 $0
|Effective start/end date||1/1/04 → 12/31/05|
- American Heart Association: $92,185.00
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