YAP/TAZ-TEAD signaling in the vocal fold

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Project Summary/Abstract Voice disorders are the most common communication disorder across the lifespan;1 nearly 20 million Americans report dysphonia annually at an annual cost of ~$13 billion when considering both treatment and lost wages.2,3 Vocal fold (VF) fibrosis is a major cause of intractable voice disorders and treatment for fibrosis is primarily empiric with only emerging biological insight to drive therapeutic decision-making. Our laboratory and others implicated Transforming Growth Factor (TGF)-β /SMAD signaling in the development of fibrosis and this pathway is likely an ideal therapeutic target for tissue fibrosis.4,5 However, SMAD signaling does not occur in isolation and SMAD inhibition results in a less favorable feedback cycle, posing a significant challenge to these targeted approaches. The Hippo signaling pathway is implicated in cell survival, differentiation, organ development, and fibrosis.6,7 Yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) have central roles in the Hippo pathway to regulate transcriptional factor activity, such as transcriptional enhanced associate domain (TEAD) family molecules. Although the Hippo pathway is modulated by soluble factors, cell-cell junctions, and extracellular matrix (ECM), these upstream signals are integrated to alter YAP/TAZ activity.8 Other signaling pathways activated in parallel with YAP/TAZ activation are integrated into the YAP/TAZ-TEAD system via direct and indirect interactions with the YAP/TAZ-TEAD complex.9,10 Since multiple pathways, including fibrotic signaling, require concurrent YAP/TAZ activation, the YAP/TAZ-TEAD complex has emerged as an attractive therapeutic target for a variety of diseases.10,11 Interestingly and of particular relevance to the VFs, tissue stiffness is a primary regulator of the Hippo pathway.12,13 Stiff ECM associated with the accumulation of highly cross-linked, fibrous ECM promotes YAP/TAZ activation. Conversely, soft ECM suppresses YAP/TAZ activity. Since tissue viscoelasticity is critical for VF function, we hypothesize Hippo signaling in the VFs contributes to organ-specific development, growth, and maintenance. Multiple signaling pathways related to fibrosis, including SMAD, Wnt, and Rho interact with the YAP/TAZ-TEAD complex and we recently reported YAP/TAZ activation mediated the fibrotic response stimulated by TGF-β/SMAD signaling in human VF fibroblasts.11,14,15 Based on our preliminary data and known Hippo functions, we hypothesize Hippo signaling is critical for development, growth, and maintenance of VF tissue. And in the context of VF injury, the activation of YAP/TAZ-TEAD signaling contributes to the fibrotic response due to altered tissue viscosity. The current proposal seeks to reveal the roles of YAP/TAZ-TEAD signaling associated with fibrotic responses in VF fibroblasts and laryngeal tissue formation using a fibroblast culture model, rat VF injury model, and gene-modified mouse. Data obtained from this study will provide a foundation for the development of new treatment approaches to be investigated in future clinical trials.