Pulmonary fibrosis is a progressive and ultimately fatal disease in which ongoing extracellular matrix (ECM) deposition and feedback biochemical and biomechanical signaling from this matrix promotes disease progression. Our published and preliminary data demonstrate that YAP and TAZ, transcriptional effectors of the Hippo pathway, are pivotal regulators of fibroblast activation in IPF, and control both ECM deposition and stiffening by fibroblasts. However, YAP and TAZ are downstream of multiple pathways, and play critical roles in multiple lung cell types, complicating efforts to target them therapeutically. Therefore we focus here on developing a fibroblast-targeted approach to YAP/TAZ inhibition. Specifically, we have identified GPCR agonism via G?s-coupled dopamine D1 Receptor (DRD1) as a fibroblast selective approach through which to inactivate YAP and TAZ. Our in vitro and in vivo preliminary data demonstrate that pharmacologic stimulation of DRD1 not only attenuates fibroblast activation, but functionally reverses their state from matrix depositing to matrix degradation and reversal of matrix stiffening. These responses depend on inhibition of YAP/TAZ, as they are lost in cells expressing constitutively active TAZ mutant protein. Published reports suggest that endogenous dopaminergic signaling is present in the normal lung; our preliminary data demonstrate that the dopamine synthetic pathway is transiently depressed during experimental fibrosis in mice, and stably reduced in the lungs of subjects with IPF. Thus, we posit the central hypothesis that dopamine signaling normally promotes fibrosis resolution after lung injury, is lost in IPF, and can be selectively targeted by DRD1 agonism to reverse experimental lung fibrosis. We propose to test this hypothesis in three specific aims, combining in vitro analysis of dopamine synthesis by lung epithelial cells and dopaminergic signaling effects on lung fibroblast function, as well as in vivo analysis of experimental fibrosis in mice in which endogenous dopamine production is lost, or exogenously augmented pharmacologically. Together the proposed studies will delineate a novel receptor mediated mechanism by which fibroblast can be switched from fibrosis promoting to fibrosis resolving states, test the therapeutic efficacy of exogenous targeting of this pathway in durable fibrosis models, and explore whether the endogenous activity of this pathway normally protects from and resolves progressive fibrosis, and is lost in human disease.
Pulmonary fibrosis is a progressive and ultimately fatal disease for which better therapeutic strategies are needed. Our published and preliminary data demonstrate that dopamine receptor stimulation modulates YAP and TAZ regulation of fibroblast activation and fibrosis, switching fibroblasts between fibrosis-promoting and fibrosis-resolving states. In this proposal we seek to develop a novel strategy by which to pharmacologically inactivate YAP and TAZ in lung fibroblasts using dopaminergic signaling, and test the capacity of this strategy to resolve persistent or progressive lung 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 |
Showing the most recent 10 out of 26 publications
