The University of Delaware’s Jason Gleghorn has received a $1.9 million grant from the National Institutes of Health to investigate pressure in lung development and congenital diaphragmatic hernia (CDH).
“CDH is a devastating structural birth defect, resulting in significant prenatal and newborn morbidity and mortality,” says Gleghorn, an assistant professor in the Department of Biomedical Engineering.
He explains that in CDH, a failure of the diaphragm to completely close allows abdominal organs to move into the chest cavity, compressing the developing lungs and resulting in often deadly pulmonary underdevelopment, or hypoplasia.
CDH occurs in about one in every 2,500 live births. About 45 percent of babies with the condition do not make it to term, 10-20 percent that are born die within weeks, and the remainder often have significant respiratory challenges.
“As the high morbidity and mortality of CDH is linked to a structural defect with no consistent genetic defect, it has been challenging to identify signaling pathways that can be targeted for treatment,” Gleghorn says.
“Treatment strategies to date have focused on surgically blocking the trachea and increasing fluid accumulation in the lung,” he adds. “However, these strategies have resulted in minimal improvement to neonatal survival rates, especially in light of the risks of any prenatal surgery.”
A major issue is poor understanding of how mechanical signals, such as the elevated pressure caused by this accumulation of fluid in the lungs, are transduced, or converted, into accelerated lung growth and the branching that occurs during normal lung development.
Gleghorn’s lab has shown that airway pressure, which depends on the function of airway smooth muscle, directly regulates the timing of branching.
With the new NIH funding, Gleghorn will focus on the molecular mechanotransduction pathways downstream of lung pressure. Specifically, they hypothesize novel mechanotransduction pathways connecting pressure to three distinct aspects of lung growth and development.
“By identifying molecular mechanisms that underlie pressure-based lung morphogenesis, we hope to provide a framework for future studies to explore mechanotransduction events central to both normal lung development and the dysregulation that occurs in CDH,” Gleghorn says. “And in the long term, we believe that the research will pave the way to identifying potential therapeutic targets that can be exploited to augment or replace current surgical treatments for CDH.”
Source : University of Delaware