Normal development of the lungs and pulmonary vasculature, and their physiological adaptation to birth, is essential for the survival of all newborn infants. One group of patients who suffer from abnormal lung and pulmonary vascular development are infants born with congenital diaphragmatic hernia (CDH). CDH is among the most common and severe of all congenital malformations with a frequency of 1 in 3500 live births and a mortality rate of 20-50%. Patients with CDH have a hole in the diaphragm allowing the abdominal organs to herniate into the chest during fetal development. As a result, the lungs and pulmonary vasculature in these patients are often underdeveloped due to a lack of sufficient space in the fetal thorax. In addition to this lack of space, our recent data demonstrate that the genetic defects responsible for abnormal diaphragm development in patients also cause abnormal development of the lungs and pulmonary vasculature. These lung-intrinsic defects result in lung hypoplasia and pulmonary hypertension that are the major cause of mortality and long- term morbidity in patients with CDH. The genetic and developmental mechanisms responsible for lung hypoplasia and pulmonary hypertension in patients with CDH are not yet understood. Furthermore, current therapies for CDH are non-specific and do not take the underlying genetic and developmental defects unique to each patient into account. Our overall hypothesis is that genetic defects in patients with CDH play a central role in the mechanisms responsible for lung hypoplasia and pulmonary hypertension. We believe that by identifying the lung-intrinsic mechanisms of abnormal development and physiological function associated with CDH, we will uncover new and more specific approaches for treatment. Our proposed experiments will address this hypothesis by determining the roles played by two key transcriptional regulators found to be mutated in patients with CDH, PBX1 and SIN3A.
The Aims of our proposal address each of the underlying mechanisms responsible for lung hypoplasia and pulmonary hypertension including: abnormal embryonic development of the lungs and pulmonary vasculature, failure of pulmonary vascular physiological adaptation to birth, and failure of postnatal lung and pulmonary vascular development.
In Aim 1 we focus on the role played by Pbx1 in postnatal lung development and pulmonary vascular physiological adaptation to birth.
In Aim 2 we focus on the role played by Sin3a in embryonic lung and pulmonary vascular development by controlling lung, vascular, and vascular smooth muscle cell proliferation and differentiation. In both Aims we will identify the downstream genetic and molecular defects caused by loss-of-function of Pbx1 or Sin3a and determine how these genetic defects cause impaired physiological function of the lungs and pulmonary vasculature. The results of our experiments will lay the groundwork for future therapeutic interventions for patients with CDH that target the specific underlying mechanisms of the disease.
Congenital diaphragmatic hernia (CDH) is a common and severe birth defect affecting 1 in 3,500 live births and with a mortality rate of 20-50%. The high rate of mortality in patients with CDH is due to abnormal development of the lungs and pulmonary vasculature causing lung hypoplasia and pulmonary hypertension for which there are no specific treatments. By investigating the genetic and developmental mechanisms responsible for lung hypoplasia and pulmonary hypertension associated with CDH, we will uncover new and more specific approaches for future therapy.
