John S. Munger, MD

Associate Professor; Director of the Honors Program. Departments of Medicine (Pulmy&CCM Div) and Cell Biology

Cell Biology, Medicine







Contact Information

341 East 25th Street
Old Public Health Building
Floor 8, Room 843A
New York, NY 10016

Tel: 212-263-3125

Research Summary

Our lab studies molecular mechanisms related to lung development and lung fibrosis. We have focused on two molecules: Transforming Growth Factor-β (TGFβ) and Sonic Hedgehog (Shh).

TGFβ is a ubiquitously produced growth factor with important roles in pathologic processes such as cancer, fibrosis and autoimmunity, and in normal development, wound repair and homeostasis. There are three TGFβ isoforms, and all are secreted in a latent form. Latency is the result of a noncovalent association of the growth factor with its propeptide, which is called latency-associate peptide (LAP). TGFβ must be released from LAP before it can bind TGFβ receptors. The activation step is highly regulated but the specific activation mechanisms involved vivo have been poorly understood.

We discovered that αvβ6, a cell surface adhesion molecule in the integrin family, can activate latent TGFβ1 and TGFβ3 by interacting with an RGD sequence in the TGFβ1 and TGFβ3 LAPs. αvβ6 is expressed in epithelia, particularly after injury. Mice lacking αvβ6 have lung inflammation and are protected from lung fibrosis due to a relative lack of TGFβ signaling in the lung (the image above shows the altered appearance of alveolar macrophages in these mice, also due to lack of TGFβ signaling). A mAb targeting this integrin is now in early clinical trials to determine efficacy in patients with lung fibrosis.

To determine the role of all RGD-binding integrins in the activation of latent TGFβ1, we made mice with a knock-in mutation of the TGFβ1 gene that changes the RGD site in LAP to RGE. These mice produce normal amounts of latent TGFβ1, but it cannot be activated by RGD-binding integrins. Strikingly, the mice have the same abnormalities seen in TGFβ1-null mice, indicating that RGD-binding integrins are indispensable for TGFβ1 activation.

A second RGD-binding integrin, αvβ8, activates TGFβ1 and TGFβ3. Mice lacking this integrin have abnormalities in vascular development. Comparison of knockouts of the two TGFβs and the two β integrin subunits reveals several partially or completely overlapping abnormalities in palate closure, immune regulation, and vascular development, suggesting that αvβ6 and αvβ8 are key TGFβ1/3 activators in vivo. We confirmed this idea by analyzing mice with combined deficiencies of αvβ6 and αvβ8 or of active TGFβ1 and TGFβ3.

Shh is a morphogen that is critical for development of the lung and other organs. It is secreted by lung epithelium and acts upon mesenchymal cells expressing the receptor Ptch1. Recent reports indicate that Shh signaling is reactivated in lungs of patients with lung fibrosis. We have shown that Shh signaling is prominent in a murine model of lung fibrosis and that inducing the overexpression of Shh in this model worsens fibrosis. We have also shown for the first time that Shh is involved in postnatal lung development, specifically in the process of alveolar septation and septal wall maturation occurring in the first 1-2 weeks after birth in mice. Our hypothesis is that Shh promotes normal alveolar wall development and fibrosis by similar mechanisms involving regulation of mesenchymal cell proliferation and/or apoptosis.