This is an application for a K08 Career Development Award studying the role of embryonic pulmonary blood flow in normal lung development and the development of lung abnormalities seen in congenital diaphragmatic hernia (CDH). CDH is a birth defect occurring in approximately 1 out of 2,500 live-born infants. In CDH, there is a defect in the diaphragm allowing persistence of abdominal viscera in the chest cavity during fetal development. CDH is associated with varying degrees of lung hypoplasia, with decreased airway branching, and specific developmental defects of the pulmonary vasculature, including increased muscularization of intrapulmonary arteries. The combination of pulmonary hypertension, secondary to the underlying abnormal pulmonary vasculature, along with pulmonary hypoplasia results in often severe respiratory distress in neonates with CDH resulting in high infant mortality of up to 40%. Furthermore, a significant proportion of CDH survivors suffer from significant long-term morbidity. The potential role of embryonic pulmonary blood flow in modulating airway branching morphogenesis and pulmonary vascular development has not been examined. Also, the molecular mechanisms responsible for the development of pulmonary hypoplasia and pulmonary vascular abnormalities in CDH are incompletely understood. The overriding hypothesis for this proposal is that normal lung airway and vascular development is specifically dependent upon adequate embryonic pulmonary blood flow and that deficiencies in embryonic pulmonary blood flow contribute to lung developmental defects in CDH. To address this hypothesis, a novel technique of ultrasound-guided in utero embryonic mouse intracardiac injection utilizing a well-described murine model of CDH will be employed to pursue the following specific aims: 1) to demonstrate the dependence of airway branching morphogenesis on embryonic pulmonary blood flow in the developing lung;2) to determine whether pulmonary arterial wall maturation is dependent upon embryonic pulmonary blood flow within the maturing vessel;and 3) to measure patterns of deficient embryonic pulmonary blood flow in CDH and determine whether defects in airway branching morphogenesis and vessel maturation in developing CDH lung are related to deficient embryonic pulmonary blood flow. Airway branching morphogenesis and pulmonary arterial wall maturation will be examined in relation to early embryonic pulmonary blood flow and tissue oxygenation in wide-type mice and in a murine model of CDH. The candidate is a pediatric surgeon who has been working closely with the mentor since becoming full-time faculty. The candidate benefits from a well-established and successful mentor and a very supportive research and practice environment. In addition, the candidate will have regular meetings with a scientific advisory committee compromised of experts in lung development and pulmonary vascular biology within the institution. The candidate's immediate goals are to obtain increased knowledge and proficiency in advanced experimental developmental biology concepts and techniques and to be able to design and conduct increasingly sophisticated experiments to address hypothesis-driven questions. The candidate's long-term goals are to become a productive independent investigator who is able to contribute significantly to the fields of developmental biology and pediatric surgery and eventually translate basic science findings back to the clinical realm. To achieve these goals a structured career development plan over the award period has been developed consisting of: gaining increased experience with advanced experimental techniques; course work;participation in conferences, symposia, and national meetings;frequent meetings with the mentor for guidance;and a gradual increase in independence over the award period.
CDH is associated with significant infant mortality and morbidity in long-term survivors. A greater understanding of the developmental mechanisms responsible for the lung defects in CDH could lead to more effective treatment options for CDH involving directed therapies, both prenatal and postnatal, toward specific mechanisms involved in airway branching and pulmonary vascular function. Also, a greater understanding of the role of early embryonic pulmonary blood flow on normal lung development may lead to a greater understanding of other lung developmental defects.
|Lath, Nikesh R; Galambos, Csaba; Rocha, Alejandro Best et al. (2012) Defective pulmonary innervation and autonomic imbalance in congenital diaphragmatic hernia. Am J Physiol Lung Cell Mol Physiol 302:L390-8|