Biophysical force affects type 1 alveolar epithelial cell-mediated regulation of the pulmonary matrisome and lung development

PROJECT SUMMARY/ABSTRACT This proposal delineates a five-year individualized training plan that will promote an independent scientific career to study the pathogenesis of bronchopulmonary dysplasia (BPD), which is the most common sequalae of prematurity and impacts the patient throughout the lifespan. Specifically, the scientific program of

the candidate will focus on how biophysical force affects type 1 alveolar epithelial cell (AT1)-mediated regulation of the pulmonary matrisome within the developing lung. The applicant is an Instructor within the Division of Neonatology and Department of Pediatrics at the Children’s Hospital of Philadelphia and has

previous training in cell and molecular biology with an emphasis on oxidative stress. Over the past several years, she has worked as a clinical research fellow in the laboratory of Dr. Edward Morrisey, a world-renowned expert in developmental biology and lung regeneration with a phenomenal record of mentorship success. The

goals of this current proposal are to acquire expertise in transcriptomics, epigenetics, and mechanobiology that will help define her future career as an NIH-funded independent investigator. To meet these goals, her and Dr. Morrisey have developed a robust training program with coursework and workshops offered by the University

of Pennsylvania and have put together a diverse advisory committee to aid her in her scientific and career development goals. Together with the outstanding environment offered by CHOP and UPenn, she is well- poised to launch into a productive and innovative research career as a physician-scientist. Recent clinical evidence suggests that the incidence of BPD is increasing as the thresholds of viability

are challenged, but the multifactorial etiology of disease pathogenesis has remained elusive. In addition, there are no treatment options which can prevent BPD or can promote pulmonary regeneration in affected neonates. The aims in this proposal will address the central hypothesis that biophysical force promotes AT1 cell

regulation of the alveolar proteosome, in part through upregulation of TGFβ signaling leading to expression of a constellation of matrisome members that are essential in maintaining alveolar health and function during neonatal lung growth and maturation. In Aim 1, the candidate will identify how elevated mechanical stress

impacts AT1 cell-mediated regulation of the pulmonary matrisome in both in vivo mechanical ventilation and in vitro cellular stretch models and examine if its effects are attenuated with loss of TGFβ. Aim 2 will characterize the effects of mechanical ventilation on the developing lung more globally, with a single-cell approach to

examine the transcriptomic and epigenetic regulatory networks as well as intercellular communication that predisposes to altered development and BPD. Successful completion of these aims will provide new insight into how AT1 cells translate applied biophysical force into changes of their own matrisome program to affect

their local environment and communicate broadly with other cell compartments to impact the normal lung developmental programming.