The Role of Developmental Dysanapsis in Lung Development Throughout the Lifespan in Experimental Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD), the chronic lung disease following preterm birth, is the most frequent complication of prematurity. Infants who develop BPD are at high risk for death and have substantial life-long morbidity. Despite decades of research, the biomechanical mechanisms that cause sustained lung development abnormalities after preterm birth and optimal strategies for the prevention and treatment of BPD remain poorly understood. Recent evidence suggests that the chronic respiratory failure of BPD may be due to disproportionate growth of lung compartments. Dysanapsis is the concept of disproportionate airway and distal lung growth. Prior work in experimental BPD has shown that intra-amniotic endotoxin causes dysanaptic growth of the airways and parenchyma in infant rats. It is unknown whether dysanaptic growth affects the trajectory of lung function over a lifetime. Given that vascular growth occurs in parallel with alveolarization during lung development, disruption of airway-airspace growth likely implies disrupted growth of the vasculature. This proposal will test whether there is persistent dysanaptic growth of airways, distal parenchyma, and vasculature in experimental BPD, and whether these structural changes contribute to persistent impaired biomechanics, pulmonary hypertension, and increased susceptibility to postnatal insults. First, we will determine whether intra-amniotic endotoxin causes dysanaptic lung growth that persists throughout postnatal lung development (Aim 1). Then, we will investigate whether impaired vascularization occurs in parallel with dysanaptic growth of the airways and parenchyma (Aim 2). Finally, we will test whether dysanaptic growth after intra- amniotic endotoxin increases the risk for worsened lung function trajectory after acute postnatal inflammation (Aim 3). In addition to expanding the understanding of interactions between airways, alveolar, and vascular growth and the long-term functional implications of dysanaptic growth, this K38 proposal would allow me to build scientific expertise early in my career. The K38 StARRTS program would provide the support and mentorship to transition from a resident physician in the R38 StARR program to a strong candidate for a future K08. My career development plan includes time to 1) advance my understanding and use of preclinical models to study lung structural development, 2) learn skills to design and perform experiments assessing vascular structure and development, 3) to perform robust and non-biased data analysis, and 4) develop strong written and oral communication skills.