Grant: Project Grant

A newborn baby's first breath is driven by the contraction of the diaphragm, a muscle we all use unconsciously thousands of time every day to aid breathing. Try to imagine what happens if the diaphragm does not form properly during pregnancy. If a hole forms in the growing diaphragm, the liver can grow up into the developing baby's chest and prevent the lungs from growing. At birth, their incomplete diaphragm and crushed lungs mean these babies have a very difficult time breathing and they require intensive care - many will not survive the first week of life. Mercifully uncommon, this birth defect is called Congenital Diaphragmatic Hernia (CDH), and its cause is unknown. The research proposed in this application is intended to answer questions surrounding the cause of CDH, and hopefully improve the health outcomes for these critically ill babies. Vitamin A is an essential part of the diet, while it is widely known for its role in vision, it is also an extremely important signaling molecule with many different roles in the body. This proposal's specific research question is uniquely focused on how problems with vitamin A signaling in the developing diaphragm may cause CDH. We aim to address this question in three novel ways: 1) develop an animal (mouse) model of CDH caused by specifically blocking how vitamin A signals in the growing diaphragm, 2) determine how important a mother's vitamin A status and intake is for susceptibility to CDH in an animal model, and 3) better understand how vitamin A signaling controls specific genes that have been associated with clinical cases of CDH. While we are using experimental models to answer our research questions, our work is guided by clinical observations. This 'bedside to bench' approach means our research is informed by actual cases of CDH, with the ultimate goal of taking new knowledge generated by our research back to the clinic to improve the outcomes of CDH.