Project Summary 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.
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