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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL120839-02
Application #
8898900
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
Richter, S; Gerum, R; Winterl, A et al. (2018) Phase transitions in huddling emperor penguins. J Phys D Appl Phys 51:
Hecker, Julian; Xu, Xin; Townes, F William et al. (2018) Family-based tests for associating haplotypes with general phenotype data: Improving the FBAT-haplotype algorithm. Genet Epidemiol 42:123-126
Andasari, Vivi; Lü, Dongyuan; Swat, Maciej et al. (2018) Computational model of wound healing: EGF secreted by fibroblasts promotes delayed re-epithelialization of epithelial keratinocytes. Integr Biol (Camb) 10:605-634
Gerum, Richard; Richter, Sebastian; Fabry, Ben et al. (2018) Structural organisation and dynamics in king penguin colonies. J Phys D Appl Phys 51:
Atia, Lior; Bi, Dapeng; Sharma, Yasha et al. (2018) Geometric constraints during epithelial jamming. Nat Phys 14:613-620
Lan, Bo; Krishnan, Ramaswamy; Park, Chan Yong et al. (2018) Transient stretch induces cytoskeletal fluidization through the severing action of cofilin. Am J Physiol Lung Cell Mol Physiol 314:L799-L807
Sharma, Yasha; Atia, Lior; Rhodes, Christalyn Sims et al. (2018) Scaling Physiologic Function from Cell to Tissue in Asthma, Cancer, and Development. Ann Am Thorac Soc 15:S35-S37
Lee, Gyudo; Atia, Lior; Lan, Bo et al. (2018) Contact guidance and collective migration in the advancing epithelial monolayer. Connect Tissue Res 59:309-315
Reynolds, Daniel S; Bougher, Kristen M; Letendre, Justin H et al. (2018) Mechanical confinement via a PEG/Collagen interpenetrating network inhibits behavior characteristic of malignant cells in the triple negative breast cancer cell line MDA.MB.231. Acta Biomater 77:85-95
Panganiban, Ronald A; Sun, Maoyun; Dahlin, Amber et al. (2018) A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis. J Allergy Clin Immunol 142:1469-1478.e2

Showing the most recent 10 out of 57 publications