The Robinette Foundation Professor of Cardiovascular Medicine
Professor of Cell and Developmental Biology
Director, Penn Center for Pulmonary Biology
Scientific Director, Penn Institute for Regenerative Medicine
Location: Smilow TRC 11-124
Admin: Christine Maschak
The goal of the Morrisey laboratory is to define the molecular mechanisms underlying pulmonary development and to determine how these mechanisms can be harnessed to improve repair and regeneration in these tissues through the harnessing of cutting edge technologies such as CRISPR mediated genome editing techniques and developing advanced bioinformatics pipelines to process, visualize and explore newly generated genomic databases. The Morrisey lab has been a leader in the study of the development and repair/regeneration of the respiratory and cardiovascular systems and has had a significant impact on the characterization of the molecular pathways governing pulmonary development through the use and in-house development of novel transgenic mouse models. The lab is composed of an international team of graduate students, postdoctoral fellows, physician scientists and highly skilled research staff who provide continuity to the lab and also provide technical infrastructure to accelerate discovery. Currently research programs include: (i) Pulmonary development and cell fate mapping, (ii) Epithelial-mesenchymal interactions in tissue repair and regeneration processes and (iii) Modeling human lung diseases in mice and in novel organotypic cultures.
Regulation of airway morphogenesis and differentiation by Wnt signaling
The major goals of this project are to define the importance of canonical and non-canonical Wnt signaling in lung epithelial development through inactivation of Fzd10, Fzd2, and Daam1 in vivo and through in vitro assays to determine how these pathways affect lung epithelial differentiation, growth, and cell migration.
Function of the IncRNA transcriptome in lung development and regeneration
This project will examine the role of long non-coding RNAs in lung development and regeneration. The information gained from these studies will provide novel and important information regarding the role of this species of RNA in regulating gene expression in the lung and the affects that disruption of these genes have on normal lung development. These are some of the first studies to explore this type of control on lung gene expression and will provide a platform of knowledge that can be used by other researchers to explore the importance of these genes in human lung biology.
Developmental pathways regulating adult lung quiescence
This project will examine the importance of maintaining cellular quiescence in the adult lung. The information gained from thesejkl; studies will provide novel insight into how cells in the lung remain quiescent during homeostasis and how disruption in quiescence affects normal adult lung function. While previous studies have examined the importance of promoting cell proliferation in the adult lung, these are some of the first studies to explore what keeps cells from proliferating. Such information will provide a novel platform to better understand this process in human diseases such as fibrosis and cancer.
Molecular pathways controlling alveolar epithelial remodeling in development and regeneration
This project will examine the pathways that regulate late lung development. The information gained will have a direct impact on our understanding of the cellular changes that occur just prior to birth and the importance of these processes in generating a functional lung. While these late stages of lung development and maturation are critical for neonatal health, little is understood about the molecular pathways that are important for their successful execution. Our studies will provide crucial information to better understand diseases of the neonate including bronchopulmonary dysplasia.
A national iPS cell network with deep phenotyping for translational research*
The UPenn iPS core has generated a large number (over 600 lines) of iPSC lines over the past several years, some of which have extensive phenotyping and genotyping data; and a few of these lines have been extensively validated for conversion into various cell lineages. We are already sharing these cell lines with our collaborators including Dr. Kotton. We will use the funds from this award to extend the sharing of our lines to an even broader community of stem cell researchers in the CTSI network.
Identification and characterization of an epithelial progenitor lineage for targeting gene correction of ABCA3 and related alveolar diseases
Editing alveolar progenitor cells for correction of monogenic disease (Project 2)
In this Project, we propose to define a unique alveolar type II (AT2) progenitor cell lineage termed AEPs in both mouse and human lungs and develop methods to target these AEP cells for correction of a monogenic lung disease, characterized by ABCA3 mutations, which will be defined in Project 1 (Whitsett). We will employ mouse genetic models and mouse and human lung organoid models to define the capabilities of AEPs to self-renew and generate functional AT2 cells.
The Center for Molecular Studies in Digestive and Liver Diseases
The Center supports four scientific cores, conferences, and a pilot program with the goal of advancing research of center members and junior faculty as well as to attract new investigators to digestive and liver topics. Dr. Morrisey is responsible for the oversight and management of the Cell Culture and iPS Core (facility) which serves the needs of the Center for Molecular Studies in Digestive and Liver Diseases through their services and technologies, a rich repository of c cell lines (2D and 3D), provides standardized protocols, and regular orientation and training.
Wnt signaling in the alveolar niche
Wnt signaling plays multifarious roles in lung development, both in epithelial and mesenchymal lineages. Little is known about the role of Wnt signaling in lung alveolar homeostatis or after acute injury. This project will define the cell specific role for Wnt signaling in both the epithelial and mesenchymal lineages of the adult alveolus.
Defining the progenitor cell interactions regulating the mouse and human lung alveolar niche
This project will investigate the alveolar compartment in the lung, which is the site of gas exchange and is required for terrestrial life. The information gained will have a direct impact on the understanding of how blood is oxygenated and how the lung responds to environmental insult and diseases and regenerates after injury. With the alveolar niche or compartment is required for breathing air, little is understood about the cell-cell interactions important for its function. The studies in this project will provide crucial information to better understand diseases that impact the lung alveolus including degenerative disorder such as chronic obstructive pulmonary disease.
- Zepp JA, Zacharias, WJ, Frank DB, Cavanaugh CA, Zhou S, Morley MP, Morrisey EE. Distinct Mesenchymal Lineages and Niches Promote Epithelial Self-Renewal and Myofibrogenesis in the Lung. Cell (2017) 6:1134-1148. PMCID: PMC5718193.
- Liu Y, Conlon DM, Bi X, Slovik KJ, Shi J, Edelstein HI, Millar JS, Javaher A, Cuchel M, Pashos EE, Iqbal J, Hussain MM, Hegele RA, Yang W, Duncan SA, Rader DJ, Morrisey EE. Lack of MTTP Activity in Pluirpotent Stemm Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress. Cell Rep (2017) 7:1456-1466. PMCID: PMC5555078.
- Frank DB, Peng T, Zepp JA, Snitow M, Vincent TL, Penkala IJ, Cui Z, Herriges MJ, Morley MP, Zhou S, Lu MM, Morrisey EE. Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-renewal and Differentiation. Cell Rep (2016) 9:2312-2325. PMCID:PMC5214982.
- Wang Y, Frank DB, Morley MP, Zhou S, Wang X, Lu MM, Lazar MA, Morrisey EE. HDAC3-Dependent Epigenetic Pathway Controls Lung Aveolar Epithelial Cell Remodeling and Spreading via mir-17-92 and TGF-β Signaling Regulation. Dev Cell (2016) 3:303-315. PMCID:PMC4750387.
- Peng T, Frank DB, Kadzik RS, Morley MP, Rathi KS, Wang T, Zhou S, Cheng L, Lu MM, Morrisey EE. Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration. Nature (2015) 526: 578-582. PMCID: PMC4713039.
- Tian Y, Liu Y, Wang T, Zhou N, Kong J, Chen L, Snitow M, Morley M, Li D, Petrenko N, Zhou S, Lu M, Gao E, Koch WJ, Stewart KM, Morrisey EE. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Sci Transl Med (2015) 7:279 PMCID: PMC25787764.