Funding outcome

When oxygen levels in a normal healthy person fall, there are mechanisms that immediately increase breathing to restore oxygen back to normal. People with unstable breathing, whether from being born prematurely, genetic disorders or sleep disordered breathing such as Obstructive Sleep Apnea, constantly experience periods where ' oxygen levels sometimes fall below normal (chronic intermittent hypoxia - CIH). CIH has immediate and long-term negative effects on health; for premature infants these range from death to life-long problems with underdeveloped lungs, and for others, fatigue and increased risk of heart disease. The challenge is that when oxygen falls in many of the patient groups with unstable breathing, their already weak breathing systems are unable to restore oxygen. This causes mechanisms in the brain to actually inhibit breathing, which makes things even worse. Most premature babies can be treated with caffeine, which stimulates breathing. However, - 20% of infants do not respond to caffeine. For them, and those suffering from the other conditions listed above there are few treatment options. New therapies -breathing stimulants - that counteract this intermittent hypoxia are desperately needed. We have recently discovered a novel mechanism in the brain that stimulates breathing when oxygen levels fall. More importantly, we have identified a candidate ion channel that we think is responsible for this stimulation. The objective of this study is to determine whether this channel underlies this novel excitation of breathing. To do so, we will isolate slices of brainstem (from neonatal rats) that continue to generate breathing in a dish and study in detail the subtypes of this ion channel that are in the breathing network as well as mechanisms by which it increases breathing. We will also change activity of this ion channel in adult rats and measure breathing, muscle and brain activity to determine whether this channel is responsible for increasing breathing when brain oxygen falls. This excitatory mechanism reduces the degree to which breathing falls and therefore limits hypoxia. We are studying each step in this naturally occurring pathway in the hope that this knowledge will reveal targets through which breathing can be stimulated to prevent the depression of breathing that occurs when brain oxygen falls and reduce exposure to the dangerous effects of chronic intermittent hypoxia.