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.
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