David B. Frank, M.D., Ph.D.
Assistant Professor of Pediatrics
Perelman School of Medicine
Children’s Hospital of Philadelphia
Contact:
Phone: 267-426-5700
Email: FRANKD@email.chop.edu
Research Overview
The goal of our lab is to discover novel molecular and cellular mechanisms underlying the multi-faceted etiologies of pediatric pulmonary hypertension (PH). As such, our approach is designed to uncover developing progenitor cell populations and their unique characteristics that orchestrate lung vascular and airway growth in normal development and maintenance in homeostasis. To accomplish this discovery, we are applying novel ex vivo modeling, advanced imaging and image process of static and live tissue, single cell and population RNA sequencing, CRISPR-Cas9 gene editing, and transgenic mouse modeling to unravel mechanisms of cardiopulmonary development and homeostasis that can be manipulated for tissue regeneration.
To accomplish this, our laboratory is focused on 3 areas of research:
1. Cell fate in alveolar lung development
The lung alveolus is composed of a diverse collection of cell types responsible for gas exchange. The alveolar epithelial and vasculature govern gas exchange and are interdependent on one another for expansion of the developing alveolus. Disruption of this process due to prematurity or injury results in not only deficits in the airway epithelium but also the vasculature leading to diseases such as PH. Given this, the discovery of mechanisms controlling the establishment of cell fate and growth in the lung alveolar epithelium may lead to improved vascular growth and prevention of PH.
2. Epithelial-endothelial interactions in lung development and homeostasis
Co-development of the lung epithelium and vasculature occurs throughout development. We are interested in the discovery of novel progenitor cell populations that orchestrate epithelial-endothelial interactions for lung growth in development. In addition, we believe similar interactions occur to maintain the lung at homeostasis and hypothesize that disruption of this relationship leads to PH.
3. Mechanisms of cell fate establishment in cardiopulmonary vasculature
Defects in the development and growth of the proximal pulmonary artery and veins are devastating co-morbidities in congenital heart disease (CHD). We know very little about the origins and molecular mechanisms underpinning their development. To expand our knowledge and identify potential novel therapeutics in pulmonary vasculature-associated CHD, we are examining the establishment of the pulmonary vasculature using single cell transcriptomic discovery and high-resolution static and live imaging to illustrate cellular and molecular mechanisms of cardiopulmonary cell fate.
Selected Publications
- Zacharias W.J.*, Frank D.B.*, Zepp J.A., Morley M.P., Alkahlell F.A., Zhou S., Cantu E., Morrisey E.E. Identification of a Wnt-responsive alveolar progenitor that regenerates the mouse and human lung. Nature 2018 Mar 8;555(7695):251-255. *Co-first author
- Swarr DT, Peranteau WH, Pogoriler J, Frank DB, Adzick NS, Hedrick HL, Morley M, Zhou S, Morrisey EE. Novel Molecular and Phenotypic Insights into Congenital Lung Malformations. Am J Respir Crit Care Med. 2018 May 15;197(10):1328-1339.
- Zepp J.A., Zacharias W.J., Frank D.B., Cavanaugh C.A., Morley M.P., Morrisey E.E. Distinct mesenchymal lineages and niches promote epithelial self-renewal and myofibrogenesis in the lung. Cell. 2017 Sep 7;170(6):1134-1148.
- Frank D.B., Peng T., Zepp J., Vincent T.L., Snitow M.S., Herriges MJ, Penkala I., Morley MP, Zhou S., Zheng C., Lu M, Morrisey E. Emergence of a wave of Wnt signaling that regulates lung alveologenesis through controlling epithelial self-renewal and differentiation. Cell Rep. 2016 Nov 22;17(9):2312-2325.
- Peng T., Frank D.B., Kakzik R.S., Morley M.P., Rathi K.S., Wang T., Zhou S., Cheng L., Lu M.M., Morrisey E.E. Hedgehog actively maintains adult lung quiescence and regulates injury repair and regeneration. Nature. 2015 Oct 5. doi: 10.1038/nature14984.
- Wang Y., Frank D.B., Morley M.P., Zhou S., Wang X., Lu M.M., Lazar M.A., Morrisey E.E. An epigenetic pathway that controls lung alveolar epithelial cell remodeling and spreading through regulation of miR-17-92 expression and TGF-b signaling. Dev Cell. 2016 Feb 8;36(3):303-15.