In this revised application we propose to bridge cutting-edge topics in biology and physics in order to create a new physical picture of collective cellular migration in lung health and disease. The projects and cores of this program focus upon a common central hypothesis: In collective behaviors of epithelial cells in the lung, di- verse physical factors and their multiple biological effects are brought together by the concept of the glass transition as described on a unifying jamming phase diagram. Each project director is a leader in his or her respective discipline. Project 1 (Weitz) will investigate basic physics at the level of the single cell in isolation (0-D), in single-file migration (1-D), and in transition to 2-D behavior. This project will emphasize the unifying role of cell volume regulation in mechanical determinants of cell jamming. Project 2 (Fredberg) will investigate basic physics of jamming in monolayers (2-D) and cell clusters (3-D). Project 3 (Drazen) will investigate the role of jamming in the bronchial epithelium as a basic mechanisms of asthma pathogenesis. Core A (Butler, Zaman, Krishnan) will support and develop novel technologies for imaging of physical forces. Core B (Weiss) will seek common molecular network motifs that span projects and characterize regions of the jamming phase diagram. Core C (Fredberg) is administrative. Together, the interdisciplinary projects and cores of this pro- gram project combine physics and biology at a level that is realized only rarely. The projects are unified by a central hypothesis that is radical, mechanistic and testable, and that has the potential to impact basic under- standing of lung injury and repair.
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