Grant: Project Grant

After a baby is born, air rushes into the lungs with its first breath - but to pick up oxygen from that breath, blood urgently has to flow to the lungs too. Newborn lung blood flow is normally triggered by the presence of oxygen. Babies who have difficult deliveries, or who don't get enough oxygen during their birth, sometimes can't get enough blood flowing to their lungs. So even when they try to breathe, they can't pick up oxygen from their breaths - and they stay blue. This disease is called newborn pulmonary hypertension. It accounts for 10% of admissions to the newborn ICU, and these blue babies are the sickest in the newborn ICU. We have some drugs to treat them, but they don't always work. Heart muscle and lung blood vessel muscles have opposite jobs at birth. The heart needs to contract harder, and lung blood vessels need to relax to let blood flow. These opposite events happen through a single system of signals inside the cell, called the adenylyl cyclase pathway. We studied effects of low oxygen levels on the function of the heart, and on muscle lining the blood vessels of the newborn lung. In low oxygen, muscles in the heart and blood vessels don't respond properly to medications. We found that adenylyl cyclase doesn't work in low oxygen. Exposure to a low oxygen level makes this enzyme slow down, like a foot on the brake of a car. That means lung blood vessels can't relax, and blood won't flow into the baby's lungs. Even after oxygen levels normalize, this enzyme doesn't resume its normal function. Many important drugs use the adenylyl cyclase system, including those we use in the ICU to make a baby's heart pump better. These drugs also stop working in low oxygen. We hope to help these babies' lungs relax to allow blood flow, and help their hearts pump against the burden, by testing the switches that turn the adenylyl cyclase molecule on and off, in animal and cell models of pulmonary hypertension, and in models of the adenylyl cyclase molecule.