miR-17~92 Haploinsufficiency Influences Alveolar and Vascular Endothelial Development

Approximately 14,000 preterm infants in the United States develop Bronchopulmonary Dysplasia (BPD) each year, often requiring prolonged respiratory support and supplemental oxygen therapy. Hallmarks of the altered lung structure present in BPD are likely related to a combination of arrested development processes of the lung and direct injury from oxygen and ventilator support. Therapies to effectively reverse or prevent this damage are not available because the cellular mechanisms responsible for the altered lung structure present in BPD are not well understood. The object of this proposal is to investigate changes that occur in cell processes and protein expression when the expression of microRNA17~92 cluster is genetically altered. Previous work in mice completely removing this cluster causes significant changes in the lungs so that pups cannot survive after birth. MicroRNAs are cellular signals, contained within the genome, that influence the expression of proteins within the cell without themselves becoming proteins. There is significant evidence that altered microRNA expression is responsible for many human diseases; of particular relevance to this project, microRNA 17~92 expression is decreased patients with BPD. The studies in this application will investigate structural and functional alterations in alveolar and pulmonary endothelial development caused by genetic decrease of the 17~92 cluster to half the normal expression. As mentored physician scientist training grant, this project will provide skills and knowledge training necessary to progress in my career toward independence and continued funding.