YAP/TAZ-TEAD signaling in the vocal fold

项目总结/摘要 语音障碍是一生中最常见的沟通障碍;1近2000万人 美国人每年报告发声困难，在考虑治疗和治疗时， 声带（VF）纤维化是难治性嗓音障碍和纤维化治疗的主要原因。 主要是经验性的，只有新兴的生物学见解才能推动治疗决策。本实验室 和其他人暗示转化生长因子（TGF）-β /SMAD信号传导在纤维化的发展中， 该通路可能是组织纤维化的理想治疗靶点。4，5然而，SMAD信号传导并不发生 在隔离和SMAD抑制导致不太有利的反馈循环，提出了一个重大的挑战， 这些有针对性的方法。Hippo信号通路与细胞存活、分化、器官分化和免疫应答有关。 6，7与PDZ结合的Yes相关蛋白（雅普）和转录共激活因子 基序（TAZ）在Hippo通路中具有调节转录因子活性的中心作用，例如 转录增强相关结构域（TEAD）家族分子。虽然河马途径是 这些上游信号受可溶性因子、细胞-细胞连接和细胞外基质（ECM）的调节， 整合以改变雅普/TAZ活性。8与雅普/TAZ激活平行激活的其它信号传导途径 通过与雅普/TAZ-TEAD的直接和间接相互作用，被整合到雅普/TAZ-TEAD系统中 由于包括纤维化信号传导在内的多种途径需要同时激活雅普/TAZ， 雅普/TAZ-TEAD复合物已成为多种疾病的有吸引力的治疗靶点10，11。 有趣的是，与VF特别相关的是，组织硬度是Hippo的主要调节因子。 途径。12，13与高度交联的纤维状ECM的积累相关的刚性ECM促进 雅普/TAZ激活。相反，软ECM抑制雅普/TAZ活性。由于组织的粘弹性是至关重要的 对于VF功能，我们假设VF中的Hippo信号传导有助于器官特异性发育，生长， 和维护与纤维化相关的多种信号传导途径，包括SMAD、Wnt和Rho， 雅普/TAZ-TEAD复合物和我们最近报道的雅普/TAZ激活介导的纤维化反应 在人VF成纤维细胞中通过TGF-β/SMAD信号传导刺激。11，14，15基于我们的初步数据和已知的 Hippo功能，我们假设Hippo信号传导对VF的发展，生长和维持至关重要 组织.在VF损伤的情况下，雅普/TAZ-TEAD信号通路的激活有助于纤维化的发生。 由于组织粘度改变而引起的反应。目前的建议旨在揭示雅普/TAZ-TEAD的作用 VF成纤维细胞中与纤维化反应相关的信号传导和使用成纤维细胞的喉组织形成 培养模型、大鼠VF损伤模型和基因修饰小鼠。从本研究中获得的数据将提供 为未来临床试验中研究新的治疗方法奠定了基础。

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.