Funding outcome

The brain depends on a constant supply of oxygen to meet its energy needs. If this supply fails for even a few minutes permanent brain damage or death can result. Some infants born prematurely are at risk because they suffer from apnea of prematurity, a condition where breathing slows or stops (apnea) for short periods and oxygen levels fall. Unstable breathing reflects that the brain circuits that produce breathing are immature. Reductions in oxygen levels during these periods of apnea trigger an adaptive increase in breathing. However, if this increase does not immediately restore oxygen levels, the brain becomes hypoxic and our research in animal models has shown that the neurochemical ATP is released in the respiratory centers of brain. While this ATP initially helps maintain the adaptive increase in breathing, ATP is rapidly degraded to adenosine. Adenosine depresses breathing. The net result is that the initial hypoxia-induced increase in ventilation is followed by a secondary depression that is potentially fatal in premature infants who suffer from apnea of prematurity. In many infants, the respiratory stimulant caffeine is used to reduce these apneas and the respiratory depression. However, ~20% of infants do not respond to caffeine so alternate treatments are required. The interaction between ATP excitation and adenosine inhibition of breathing is emerging as key in determining the magnitude of the hypoxic depression. Multiple factors determine the balance between the actions of ATP and adenosine including i) enzymes that degrade ATP into adenosine; ii) transporters that remove adenosine from the space around neurons, and: iii) an intracellular enzyme (adenosine kinase) that keeps adenosine levels low inside cells so that transporters can move adenosine down its concentration gradient from outside to inside cells and stop its inhibitory actions. The potential role of adenosine kinase in the hypoxic ventilatory response has never been examined. However, dysfunction of this enzyme and the resulting disruption of adenosine levels is a key factor in generation of seizure activity in cortical regions of the brain: i.e., adenosine kinase is a key regulator of adenosine levels in other brain areas. The aim of this proposal is to determine the role of adenosine kinase in the hypoxic ventilatory response and in controlling the balance between the actions of ATP and adenosine in the region of the brain the generates breathing. This information will inform development of strategies to shift the balance between ATP and adenosine signaling in favor of excitation to counteract the life-threatening hypoxic respiratory depression.