The mechanical environment profoundly influences the structure and function of the lung, from branching morphogenesis and cellular differentiation in the developing lung, to growth, injury, and remodeling of the mature organ. The underlying molecular mechanisms by which cells sense and respond to their mechanical environment remain elusive. Recently obtained evidence demonstrates that the intercellular spaces separating airway epithelial cells are highly deformable under physiological loads. These intercellular spaces are the site of putative autocrine signaling loops involving the epidermal growth factor receptor (EGFR) and its ligands. Physiological levels of mechanical stress applied to airway epithelial cells, both in vitro and in situ, trigger signaling through the EGFR pathway. Integration of these observations leads to the following central hypothesis: mechanical stress can be transduced through the steady-state activity of an autocrine EGFR loop operating in a dynamically regulated intercellular space. This hypothesis will be tested in the following three specific aims using primary human airway epithelial cultures: (1) establish the molecular components and constitutive functionality of the autocrine signaling loop in the epithelial intercellular space; (2) define the dynamic biophysical response of the intercellular space to physiologically relevant loading conditions; and (3) use biochemical and computational tools to test the central hypothesis, then explore its biological role in modulating the expression of mucSAC, a marker of the mucus secretory phenotype upregulated in various airway disorders. The resulting insights could establish a new and unanticipated paradigm for mechanotransduction occurring in the extracellular space, and change our view of how mechanical forces contribute to the biology of the airways in health and disease. The lung experiences a range of mechanical forces during normal (e.g breathing) and disease (e.g. asthma) conditions, influencing lung structure and function. The proposed studies will explore how the cells that line the airways sense and respond to changes in their mechanical environment. These studies will provide a framework for understanding and modulating mechanical responses in the lung.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL082856-03
Application #
7337291
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Croxton, Thomas
Project Start
2006-01-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
3
Fiscal Year
2008
Total Cost
$358,299
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
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Tschumperlin, Daniel J; Boudreault, Francis; Liu, Fei (2010) Recent advances and new opportunities in lung mechanobiology. J Biomech 43:99-107
Kojic, Nikola; Huang, Austin; Chung, Euiheon et al. (2010) A 3-D model of ligand transport in a deforming extracellular space. Biophys J 99:3517-25
Park, Jin-Ah; Drazen, Jeffrey M; Tschumperlin, Daniel J (2010) The chitinase-like protein YKL-40 is secreted by airway epithelial cells at base line and in response to compressive mechanical stress. J Biol Chem 285:29817-25
Kojic, Nikola; Chung, Euiheon; Kho, Alvin T et al. (2010) An EGFR autocrine loop encodes a slow-reacting but dominant mode of mechanotransduction in a polarized epithelium. FASEB J 24:1604-15
Boudreault, Francis; Tschumperlin, Daniel J (2010) Stretch-induced mitogen-activated protein kinase activation in lung fibroblasts is independent of receptor tyrosine kinases. Am J Respir Cell Mol Biol 43:64-73
Park, Jin-Ah; Tschumperlin, Daniel J (2009) Chronic intermittent mechanical stress increases MUC5AC protein expression. Am J Respir Cell Mol Biol 41:459-66
Kojic, Nikola; Huang, Austin; Chung, Euiheon et al. (2008) Quantification of three-dimensional dynamics of intercellular geometry under mechanical loading using a weighted directional adaptive-threshold method. Opt Express 16:12403-14