At birth, pulmonary vasodilatation occurs in association with an increase in 02 tension, ventilation, and shear stress. When pulmonary artery (PA) pressure does not decrease, persistent pulmonary hypertension of the newborn (PPHN) results. PPHN is characterized by increased pulmonary vascular tone and reactivity, severe central hypoxemia, and an incomplete response to supplemental 02. While the mechanisms responsible for perinatal pulmonary vasodilatation are incompletely understood, recent data indicate that postnatal adaptation of the pulmonary circulation is contingent upon calcium-sensitive K+ (KCa) channel activation. Insight into the molecular mechanism of several 02 sensing systems has demonstrated that a universal response to reduced 02 availability involves the expression and activity of Hypoxia-lnducible Factor 1(HIF-1), a transcriptional activator of genes involved in 02 delivery or metabolic adaptation to hypoxia. At least two KCa channel subunit genes possess putative HIF-1 response elements. Taking these observations together, we propose to test the working hypothesis that the low oxygen tension environment of the normal fetus increases pulmonary vascular KCa channel expression, through HIF-1 mediated transcriptional regulation.
The specific aims are to test the following hypotheses:
Aim 1. Hypoxia modulates KCa channel subunit expression in the perinatal pulmonary circulation;
and Aim 2. Hypoxia modulates KCa channel gene expression through Hypoxia-lnducible Factor 1. Identification of the mechanisms responsible for KCa channel expression in the perinatal pulmonary circulation may provide a specific molecular target for novel therapeutic approaches to PPHN, an ongoing cause of neonatal morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL070628-04
Application #
7438608
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Gail, Dorothy
Project Start
2003-08-01
Project End
2009-12-31
Budget Start
2007-06-25
Budget End
2009-12-31
Support Year
4
Fiscal Year
2005
Total Cost
$285,289
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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