Researchers in NYU Langone’s Division of Pulmonary, Critical Care, and Sleep Medicine investigate lung development, fibrosis, and signaling pathways.

Signaling Pathways and Sonic Hedgehog

Principal investigators Matthias C. Kugler, MD, and John S. Munger, MD, are interested in signaling pathways relevant to lung development and fibrosis. Dr. Munger and collaborators showed that the integrin αvβ6 activates transforming growth factor β (TGF-β), and that this mechanism underlies the role of TGF-β in lung fibrosis and major developmental processes. Dr. Kugler participated in seminal studies of epithelial–mesenchymal transition, TGF-β signaling, and integrin function in pulmonary fibrosis before his residency and fellowship training at NYU Langone.

These researchers combine their interests in current studies of sonic hedgehog (Shh) signaling in the lung. Sonic hedgehog is a secreted protein that signals through the Patched 1 receptor, Smoothened, and the Gli transcription factors.

As a morphogen, Shh plays a crucial role in the development of the lung and many other organs. Sonic hedgehog signaling also maintains adult stem cells in tissues such as those in the brain and skin and is involved in several cancers. In humans, Shh signaling has been implicated in fibrosing lung diseases as well as in chronic obstructive pulmonary disease and asthma.

Using mouse models, Dr. Kugler and Dr. Munger study the role of Shh pathway signaling in the postnatal development of the lung. Their experiments reveal roles for Shh in regulating the structural properties of the lung, the formation of new alveolar septa, and the formation of alveolar myofibroblasts. They are currently using single-cell sequencing to further define the cell types regulated by Shh.

They also evaluate Shh signaling pathways in lung fibrosis, using a mouse model of bleomycin-induced lung injury. This model allows them to investigate the Shh pathway in the regulation of mesenchymal stem cells and the importance of canonical Shh signaling, as compared with noncanonical Shh signaling.

Research Goals

Dr. Kugler and Dr. Munger have two main research goals:

• to better understand the molecular signatures of pulmonary fibrosis in pathophysiologically relevant mouse models, in order to elucidate novel mechanisms and improve treatments
• to develop a model in which factors that are present early on in life, such as the Shh pathway, can be tested alone and in combination for their ability to promote development of structural derangements such as pulmonary fibrosis and chronic obstructive pulmonary disease (COPD) in adult life, with the hypothesis that multiple alterations occur to reprogram the lung from normal homeostasis to disease

Resources that are available in this laboratory for division fellows include mouse model systems, histology and microscopy techniques, single-cell sequencing techniques, lung morphometry methods, and cell culture techniques.

Recent Publications

Kugler MC … Munger JS. The Hedgehog target Gli1 is not required for bleomycin-induced lung fibrosis. Exp Lung Res. 2019. DOI.

Kugler MC … Munger JS. Sonic Hedgehog signaling regulates myofibroblast function during alveolar septum formation in murine postnatal lung. Am J Respir Cell Mol Biol. 2017. DOI.

Kugler MC … Munger JS. Sonic Hedgehog signaling in the lung. From development to disease. Am J Respir Cell Mol Biol. 2015. DOI.

Liu L … Munger JS. Hedgehog signaling in neonatal and adult lung. Am J Respir Cell Mol Biol. 2013. DOI.