YAP/TAZ-TEAD signaling in the vocal fold

声带中的 YAP/TAZ-TEAD 信号传导

• 批准号: 10810968
• 负责人: Ryosuke Nakamura
• 金额: $ 46.61万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810968
• 关键词: Address; American; Biochemical Phenomena; Biochemical Process; Biological; Cell Survival; Cells; ChIP-seq; Clinical Trials; Communication impairment; Complex; Data; Decision Making; Development; Disease; Dysphonia; Event; Extracellular Matrix; Family; Feedback; Fibroblasts; Fibrosis; Foundations; Funding; Future; Gene Expression; Gene Modified; Genes; Genetic Transcription; Genotype; Growth; Health; Histological Techniques; Homeostasis; Human; Hyaluronic Acid; Iatrogenesis; Immunohistochemistry; In Vitro; Injury; Intercellular Junctions; Laboratories; Larynx; Literature; Longevity; MADH7 gene; Maintenance; Mediating; Modeling; Molecular; Mus; Myofibroblast; NR4A1 gene; Nuclear; Nuclear Receptors; Organ; Outcome; Pathway interactions; Patients; Process; Proteins; Rattus; Reporting; Role; Signal Pathway; Signal Transduction; System; Therapeutic; Tissues; Transcriptional Coactivator with PDZ-Binding Motif; Transforming Growth Factor beta; Transgenic Mice; Viscosity; Voice; Voice Disorders; Wages; Wild Type Mouse; connective tissue growth factor; cost; crosslink; disability; iatrogenic injury; in vivo; inhibitor; injured; innovation; insight; mouse model; novel therapeutic intervention; novel therapeutics; organ growth; response; response to injury; rho; therapeutic target; transcription factor; transcriptome sequencing; viscoelasticity; vocal cord; wound closure

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.

项目摘要/摘要 语音障碍是一生中最常见的沟通障碍；1近2000万 美国人每年报告发音困难，考虑到治疗和治疗，每年的费用约为130亿美元 2，3声带(VF)纤维化是顽固性发音障碍和纤维化治疗的主要原因 主要是经验性的，只有新兴的生物学洞察力才能驱动治疗决策。我们的实验室 另一些研究表明转化生长因子-β/SMAD信号转导通路参与了肝纤维化的发生和发展。 这一途径可能是组织纤维化的理想治疗靶点。4，5然而，SMAD信号转导不发生 隔离和SMAD抑制会导致不太有利的反馈周期，对 这些有针对性的方法。河马信号通路与细胞存活、分化、器官 6，7是相关蛋白(YAP)和转录共激活因子与PDZ结合 Motif(TAZ)在河马途径中起核心作用，调节转录因子的活性，如 转录增强相关结构域(TEAD)家族分子。尽管河马的路径是 受可溶性因子、细胞间连接和细胞外基质(ECM)的调节，这些上游信号是 整合以改变YAP/TAZ活性。8与YAP/TAZ激活并行激活的其他信号通路 通过与YAP/TAZ-TEAD的直接和间接交互作用集成到YAP/TAZ-TEAD系统中 由于包括纤维化信号在内的多条通路需要同时激活YAP/TAZ，因此 YAP/TAZ-TEAD复合体已成为多种疾病的有吸引力的治疗靶点。 有趣的是，与VFS特别相关的是，组织硬度是河马的主要调节因素 途径：12，13僵硬的ECM与高度交联的纤维性ECM的积累有关，促进 YAP/TAZ激活。相反，软ECM抑制YAP/TAZ活性。由于组织粘弹性是至关重要的 对于VF功能，我们假设VFS中的河马信号有助于器官的特定发育，生长， 和维护。多种与纤维化相关的信号通路相互作用，包括SMAD、Wnt和Rho YAP/TAZ-TEAD复合体和我们最近报道的YAP/TAZ激活介导了纤维化反应 受转化生长因子-β/SmadD信号刺激的人室颤成纤维细胞。 河马的功能，我们假设河马信号对VF的发育、生长和维持至关重要 组织。在室颤损伤的背景下，YAP/TAZ-TEAD信号的激活参与了纤维化的发生 由于组织粘度改变而产生的反应。目前的提案试图揭示YAP/TAZ-TEAD的作用 VF成纤维细胞和使用成纤维细胞的喉组织形成中与纤维化反应相关的信号 培养模型、大鼠VF损伤模型、基因修饰小鼠。从这项研究中获得的数据将提供 为开发新的治疗方法奠定基础，以便在未来的临床试验中进行研究。