The signaling mechanisms regulating pulmonary circulatory adaptation at birth and those contributing to the development of pulmonary hypertension (PH) in infants are incompletely understood and are the long-term objectives of my laboratory. This proposal addresses the hypothesis that interactions between heat shock protein 90 (Hsp90) and its client signaling proteins regulate vascular responses in the normal newborn pulmonary circulation, that maturational changes in Hsp90/client protein interactions contribute to early postnatal pulmonary circulatory adaptation, and that chronic hypoxia alters Hsp90/client protein interactions disrupting the maturation and function of dilator signaling pathways in the neonatal lung. Physiological measurements and biochemical techniques will be used to address the following specific aims: (1A) Determine the impact of Hsp90/client protein interactions on vascular function and signaling in the lungs of newborn piglets, (1B) Determine the maturational changes in Hsp90/client protein interactions that occur between day of life 2-4 and 12-14 in healthy piglets raised in normoxia and (2) Determine the derangements in Hsp90/client protein interactions that contribute to altered vascular reactivity and signaling in the lungs of piglets with PH induced by chronic (10 days) hypoxia. Our investigations focus on interactions between Hsp90 and its known client proteins, endothelial nitric oxide synthase (NOS) and Akt kinase, as well as novel interactions with cytosolic prostaglandin E2 synthase and thromboxane synthase. At the core of our methodology is measurement of vascular responses in cannulated pulmonary resistance arteries isolated from healthy piglets and piglets with hypoxia-induced PH. PH that develops secondary to chronic pulmonary or cardiac conditions is rarely responsive to currently available therapies and is frequently lethal. These studies will improve understanding of the neonatal pulmonary hypertensive response to chronic hypoxia and are critical to the formulation of novel treatment strategies for infants with PH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075511-03
Application #
7215743
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Blaisdell, Carol J
Project Start
2005-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$354,315
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Fike, Candice D; Sidoryk-Wegrzynowicz, Marta; Aschner, Michael et al. (2012) Prolonged hypoxia augments L-citrulline transport by system A in the newborn piglet pulmonary circulation. Cardiovasc Res 95:375-84
Fike, Candice D; Aschner, Judy L; Slaughter, James C et al. (2011) Pulmonary arterial responses to reactive oxygen species are altered in newborn piglets with chronic hypoxia-induced pulmonary hypertension. Pediatr Res 70:136-41
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Fike, Candice D; Pfister, Sandra L; Slaughter, James C et al. (2010) Protein complex formation with heat shock protein 90 in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiol Heart Circ Physiol 299:H1190-204
Vadivel, Arul; Aschner, Judy L; Rey-Parra, Gloria J et al. (2010) L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Pediatr Res 68:519-25
Reese, Jeff; O'Mara, Patrick W; Poole, Stanley D et al. (2009) Regulation of the fetal mouse ductus arteriosus is dependent on interaction of nitric oxide and COX enzymes in the ductal wall. Prostaglandins Other Lipid Mediat 88:89-96
Aschner, Judy L; Zeng, Heng; Kaplowitz, Mark R et al. (2009) Heat shock protein 90-eNOS interactions mature with postnatal age in the pulmonary circulation of the piglet. Am J Physiol Lung Cell Mol Physiol 296:L555-64
Dennis, Kathleen E; Aschner, J L; Milatovic, D et al. (2009) NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiol Lung Cell Mol Physiol 297:L596-607
Fike, Candice D; Slaughter, James C; Kaplowitz, Mark R et al. (2008) Reactive oxygen species from NADPH oxidase contribute to altered pulmonary vascular responses in piglets with chronic hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 295:L881-8

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