? ? The pulmonary hypoplasia associated with developmental diaphragmatic defects causes a high degree of mortality and morbidity. The pathogenesis and developmental relationship between diaphragmatic defects and pulmonary hypoplasia is poorly understood. In a mutagenesis screen of late gestation embryos, we identified a mouse line with abnormal diaphragmatic muscularization and pulmonary hypoplasia secondary to a mutation in Fog2. Lungs from Fog2 null mice are hypoplastic with agenesis of the accessory lobe. We found a de novo FOG2 heterozygote nonsense mutation in a baby who died on the first day of life with severe pulmonary hypoplasia and a diaphragmatic defect. As this work demonstrates that FOG2 is the first known cause of diaphragmatic defect and pulmonary hypoplasia in the human, understanding the mechanisms by which Fog2 contributes to normal diaphragmatic and lung development will provide valuable insight into the pathogenesis of these congenital defects.
In Aim 1, the role of Fog2 in muscle migration to the diaphragm will be studied.
In Aim 2, the mechanism by which lack of Fog2 results in accessory lobe agenesis will be explored through temporal-spatial analysis of branching genes in early embryonic lung explants of Fog2 null mice.
In Aim 3, the human genes, FOG2 and GATA 4/5/6 will be sequenced in patients with congenital diaphragmatic defects and pulmonary hypoplasia. The candidate is a pediatric intensivist with an interest in the pathogenesis of diaphragmatic and pulmonary lesions related to congenital diaphragmatic hernia (CDH). She has had a long standing interest in becoming a physician scientist and seeks a formal, mentored training program to develop the skills necessary to become a successful independent investigator. Her proposed training program includes mentorship and collaborations with successful leaders in the field of genetics, pulmonary biology, and congenital diaphragmatic hernia. She is a well supported candidate who will benefit highly from a Clinical Scientist Development Award. ? ?
