Grants and Contracts Details
Description
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.
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11. Amount Requested: $65,000
Year 1
$65,000
Year2
$65,000
Year 3
$65,000
Year 4
$0
Status | Finished |
---|---|
Effective start/end date | 1/1/04 → 12/31/07 |
Funding
- American Heart Association: $65,000.00
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