Funding outcome

In humans, breathing begins even before a baby is born and continues throughout our entire lives. Specific centres in the brain control breathing, and with the help of special chemical sensors ensure the brain and body have enough oxygen to meet energy demands. If the brain does not have enough oxygen, for even a few minutes, permanent damage or death can result. To counter this, the body has responses that will protect against falling brain oxygen levels. When oxygen drops, the body first increases breathing. If this increase does not restore oxygen levels, there is a secondary depressive phase during which unknown brain mechanisms cause breathing to fall. This is called the secondary depression phase. In breathing control centres of the brain, a neurochemical messenger called adenosine triphosphate (ATP) is released during this second phase, which stimulates breathing and counteracts the depression. However, after it is released, ATP is broken down into its building blocks which include adenosine. Adenosine, in contrast to ATP, inhibits breathing. This suggests there is a balance between the excitatory actions of ATP and inhibitory actions of adenosine that determines the overal level of breathing during exposure to low oxygen. In premature mammals, the secondary decrease in breathing evoked by low oxygen is much greater that the excitation, and can cause breathing to stop altogether. In the clinic, premature infants with unstable breathing (apnea of prematurity, AOP) are given caffeine, a drug that blocks the inhibitory actions of adenosine, to restore their breathing and prevent these life-threatening periods when breathing can stop. Yet caffeine does not restore breathing in -20% of infants with AOP so other ways of blocking the inhibitory actions of low oxygen on breathing are required. My project is focussed on understanding the reasons why the inhibitory actions of adenosine on breathing are so much more powerful in premature mammals. I will first test whether the brain centre that controls breathing is more sensitive to adenosine in premature vs older rodents. I will then explore how all the factors that control the levels of adenosine in the brain change during development. These include enzymes that breakdown ATP to produce adenosine, transporters that remove adenosine from outside cells (where it is inhibitory) and enzymes inside cells that breakdown adenosine so it can be removed the space outside cells. We believe that these systems are not fully developed in the brain of premature babies, which allows adenosine to stick around longer and more powerfully inhibit breathing. Understanding these differences may guide development of new treatments for counteracting the inhibitory, life-threatening effects of low oxygen in premature infants.