The peripheral arterial chemoreceptors in the carotid body are critical in regulating ventilation in response to changes in oxygen tension, and they provide essential sensory input during early development to stabilize and maintain breathing throughout life. Exposure to chronic hypoxia and hyperoxia (oxygen stress) during early postnatal development significantly depresses ventilatory responses to acute hypoxia in both newborn animals and human infants born prematurely. This ventilatory depression can be life-long in animals exposed to chronic hyperoxia and only partially reversible in animals exposed to chronic hypoxia during early postnatal development. Premature infants are particularly vulnerable to the effects of hyperoxia since antioxidant defenses are reduced. Furthermore, these infants are at high risk for persistent apnea and bradycardia, reduced arousal responses during sleep, and sudden death which are all adverse physiological events related to perturbations in chemoreceptor function. Adenosine modulates chemoreceptor activity and has been shown in other model systems to be critically important in mediating cytoprotection from oxidative stress. This proposal will test the overall hypothesis that oxygen stress (hypoxia and hyperoxia) during early postnatal development depends on the presence of functional adenosine A1 and A2a receptors on type 1 cells and sensory neurons in the carotid body, and the long term response of oxygen stress perturbs the balance of excitatory and inhibitory adenosine mechanisms resulting in decreased excitability of first order sensory neurons thereby blunting chemoreceptor responses. We will interrrogate this hypothesis with 3 specific aims that will determine the effect of development on 1) the functional neuoranatomy of the adenosine system in the carotid body, 2) the correlation between hypoxic induced adenosine and ATP release (measured with novel biosensors) with single-unit sensory nerve activity, 3) the perturbations induced by chronic hypoxic and hyperoxic exposure (in vivo) on both the ultrastructure of carotid body and alterations in the adenosine neuromodulator system, 4) the role of reactive oxygen species, nuclear factor - kB, and adenosine receptors in mediating hyperoxic induced cytotoxicty (ex vivo) in the carotid body and sensory neurons.
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