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 the 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 respiratory depression. However, ~20% of infants do not respond to caffeine so alternative treatments are required. The interaction between ATP excitation and adenosine inhibition of breathing is emerging as a key determinant of the magnitude of the hypoxic depression. Multiple factors determine the balance between the actions of ATP and adenosine. Key among these is a family of enzymes called ectonucleotidases that remove phosphates from ATP (adenosine triphosphate) and degrade it to ADP (adenosine diphosphate), AMP and adenosine. There are 4 main subtypes of ectonucleotidases in the brain - each has differential substrate preferences and products (i.e., some degrade ATP to ADP, others degrade ATP all the way to adenosine). Thus, during hypoxia when ATP is released in the respiratory regions of the brain, the complement and concentration of enzymes in that region will determine the rate at which ATP breaks down and type of ATP breakdown products that accumulate. Enzymes that preferentially produce ADP foster excitation of breathing because ADP is like ATP and stimulates breathing. Enzymes that produce adenosine will promote respiratory depression. The aim of this proposal is to determine the activities of the different ATP-degrading enzymes in the respiratory regions of the brain compared to other brain regions during development. This information is necessary to guide the development of approaches that will allow manipulation of ATP degrading enzymes in respiratory regions of the brain to reduce the depressant effects of hypoxia on breathing in newborns.