Fibrosis is a pathobiological process common to many tissues and diseases which results in tissue remodeling and loss of function, often necessitating organ replacement or leading to end-stage disease. No therapies are currently available that successfully arrest or reverse fibrosis, and this represents a significant unmet clinical need. Fibrosis occurs predominantly in soft tissues (lung, liver, kidney, heart, skin) through excess fibroblast activation to a contractile/proliferative/apoptosis resistant state and accompanying deposition of extracellular matrix. We have discovered that fibroblasts are exquisitely sensitive to alterations in matrix stiffness; this finding is true for both normal and disease-derived fibroblasts, and spans the stiffness range found in normal and fibrotic lung tissue. In this project, we seek to dissect a novel molecular pathway linking matrix stiffness to fibroblast activation, and test whether this pathway is relevant in human fibrosis and essential in driving fibrosis in model systems. We focus on the transcriptional co-activators YAP and TAZ, evolutionarily conserved regulators of organ size, cell cycle, and stem cell function. Our preliminary data demonstrate enhanced nuclear localization of YAP/TAZ in human IPF tissue, and strongly support an essential role for YAP and TAZ in fibroblast activation downstream of both matrix stiffness and TGF-beta, two pivotal regulators of fibroblast biology. We hypothesize that YAP and TAZ are mechanically activated regulators of lung fibrosis that coordinate and integrate fibroblast matrix stiffness and biochemical responses leading to a cascade of pro-fibrotic functions that drive progressive fibrosis. We will evaluate this hypothesis in two aims using in vitro, mouse and human tissue models relevant to human disease. The proposed studies will advance the field by elucidating a novel point of convergence linking mechanical and biochemical cues to fibroblast activation and pulmonary fibrosis. If successful, the proposed studies could lead to new avenues for development of therapies targeting YAP and TAZ in fibrosis of the lung and other soft tissues.
The prognosis for patients with pulmonary fibrosis remains overwhelmingly negative, and new directions for therapeutic development are sorely needed. In particular, the fibroblast and its transition to an activated proliferative, contractile and matrix synthetic state appears to be a key target for therapeutic development. The proposed studies will investigate a new pathway through which mechanical and biochemical stimuli converge to activate fibroblasts and promote pulmonary fibrosis.
| Oh, Raymond S; Haak, Andrew J; Smith, Karry M J et al. (2018) RNAi screening identifies a mechanosensitive ROCK-JAK2-STAT3 network central to myofibroblast activation. J Cell Sci 131: |
| Haak, Andrew J; Tan, Qi; Tschumperlin, Daniel J (2018) Matrix biomechanics and dynamics in pulmonary fibrosis. Matrix Biol 73:64-76 |
| Dodi, Amos E; Ajayi, Iyabode O; Chang, Christine et al. (2018) Regulation of fibroblast Fas expression by soluble and mechanical pro-fibrotic stimuli. Respir Res 19:91 |
| Tschumperlin, Daniel J; Ligresti, Giovanni; Hilscher, Moira B et al. (2018) Mechanosensing and fibrosis. J Clin Invest 128:74-84 |
| Haak, Andrew J; Girtman, Megan A; Ali, Mohamed F et al. (2017) Phenylpyrrolidine structural mimics of pirfenidone lacking antifibrotic activity: A new tool for mechanism of action studies. Eur J Pharmacol 811:87-92 |
| Schafer, Marissa J; White, Thomas A; Iijima, Koji et al. (2017) Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 8:14532 |
| Jorgenson, Amy J; Choi, Kyoung Moo; Sicard, Delphine et al. (2017) TAZ activation drives fibroblast spheroid growth, expression of profibrotic paracrine signals, and context-dependent ECM gene expression. Am J Physiol Cell Physiol 312:C277-C285 |
| Sicard, Delphine; Fredenburgh, Laura E; Tschumperlin, Daniel J (2017) Measured pulmonary arterial tissue stiffness is highly sensitive to AFM indenter dimensions. J Mech Behav Biomed Mater 74:118-127 |
| Tjin, Gavin; White, Eric S; Faiz, Alen et al. (2017) Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis. Dis Model Mech 10:1301-1312 |
| Dieffenbach, Paul B; Haeger, Christina Mallarino; Coronata, Anna Maria F et al. (2017) Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2. Am J Physiol Lung Cell Mol Physiol 313:L628-L647 |
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