Grant: Operating Grant

Adequate ventilation and breathing pattern under normal conditions and in response to hypoxic (low oxygen level) exposure depend on the activity of carotid bodies, the main peripheral sensors of arterial oxygen and carbon dioxide levels, located in the neck at the bifurcation of the common carotid artery. At birth, this system is immature and consequently irregularities of the breathing pattern (apneas) are common, particularly in preterm neonates. Several factors may delay or facilitate the development of this system, and recognizing these factors and how they act, is a field of particular importance for neonatal health. This proposal focuses on progesterone, known as a potent respiratory stimulant in adults. Maternal progesterone is transferred to fetuses and newborn through the placenta during pregnancy and the milk during breast-feeding, and it has been suggested that progesterone might have a role in fetal and newborn development. My previous studies have demonstrated that progesterone administration in newborn rats decreases apnea frequency, and increases the respiratory response to hypoxia (the main response elicited by carotid bodies) in newborn rats. Preliminary results obtained in-vitro show that progesterone directly enhances the response of the carotid bodies to hypoxia, while mifepristone (a blocker of biological effect of progesterone) drastically reduces hypoxic ventilatory response, and peripheral chemoreceptor response to hypoxia in vitro. This lead to our main hypothesis, that endogenous progesterone is a critical factor for development of chemoreceptor function. This proposal has been designed to test this hypothesis by using both in-vivo and in-vitro studies in rats exposed to progesterone or mifepristone during postnatal development, and in transgenic mice that lack the progesterone receptor.