Consequences of Neonatal Hypoxia

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DESCRIPTION (provided by applicant): It is being increasingly recognized that 50% of prematurely born infants suffer with recurrent apneas that can be often fatal. Apneas are associated with intermittent hypoxemia. Hypoxia is sensed by the carotid bodies and the ensuing reflexes are critical for maintaining homeostasis. However, in neonates, carotid bodies and chemoreflex pathway are immature. The overall goal of the proposed research is to understand the consequences of neonatal hypoxemia on carotid bodies and ventilatory response to hypoxia. Based on our preliminary data, we hypothesize that: a) neonatal intermittent hypoxia promotes the developmental maturity of carotid bodies, which in turn improves ventilatory response to hypoxia, and b) IH-induced maturational changes in the carotid body involve increased generation of reactive oxygen species (ROS) leading to alterations in excitability and/or [Ca2+]i homeostasis and/or transmitter mechanisms in the glomus cells. We propose to test these hypotheses on neonatal rat pups because they resemble immature infants in terms of neuronal maturity. An integrated approach will be employed using a repertoire of techniques ranging from ventilatory measurements in intact animals to sensory activity measurements from carotid body to ion channel and transmitter measurements in isolated glomus cells. Experiments proposed in Aim 1 define the factors that contribute to IH-induced maturity of the carotid body sensitivity to hypoxia. Protocols in Aim 2 determine ventilatory patterns in IH-conditioned rat pups and assess the potential contribution of carotid bodies. Experiments in Aim 3 are aimed at assessing the cellular mechanism(s) underlying IH-induced developmental maturation of carotid body function and determine potential role of ROS. Understanding the consequences of neonatal IH provide insights into how neonatal intermittent hypoxia caused by recurrent apneas affects the ventilation in premature infants. Experimental Animal Model: Rat Pups.