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.

项目概要/摘要 声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，考虑到治疗和治疗，每年花费约 130 亿美元 工资损失。2,3 声带 (VF) 纤维化是顽固性嗓音疾病和纤维化治疗的主要原因 我们的实验室主要是经验性的，只有新兴的生物学见解来推动治疗决策。 等人指出转化生长因子 (TGF)-β /SMAD 信号传导参与纤维化和纤维化的发展 该通路可能是组织纤维化的理想治疗靶点。4,5 然而，SMAD 信号传导不会发生 孤立地和 SMAD 抑制会导致不太有利的反馈循环，这对 这些有针对性的方法与细胞存活、分化、器官有关。 发育和纤维化。6,7 Yes 相关蛋白 (YAP) 和具有 PDZ 结合的转录共激活因子 基序 (TAZ) 在 Hippo 通路中具有调节转录因子活性的核心作用，例如 尽管 Hippo 途径是转录增强关联域 (TEAD) 家族分子。 这些上游信号受到可溶性因子、细胞间连接和细胞外基质 (ECM) 的调节 整合以改变 YAP/TAZ 活性。8 其他信号通路与 YAP/TAZ 激活同时激活 通过与 YAP/TAZ-TEAD 的直接和间接交互集成到 YAP/TAZ-TEAD 系统中 复杂。9,10 由于包括纤维化信号传导在内的多种途径需要同时激活 YAP/TAZ，因此 YAP/TAZ-TEAD 复合物已成为多种疾病的有吸引力的治疗靶点。10,11 模糊且与 VF 特别相关的组织硬度是 Hippo 的主要调节因素 12,13 与高度交联的纤维 ECM 积累相关的僵硬 ECM 促进 YAP/TAZ 离线激活，软 ECM 抑制 YAP/TAZ 活性，因为组织粘弹性至关重要。 对于 VF 功能，我们勇敢地认为 VF 中的 Hippo 信号传导有助于器官特异性发育、生长、 与纤维化相关的多种信号通路，包括 SMAD、Wnt 和 Rho 相互作用。 YAP/TAZ-TEAD 复合物，我们最近报道 YAP/TAZ 激活介导纤维化反应 受人 VF 成纤维细胞中 TGF-β/SMAD 信号传导的刺激。11,14,15 基于我们的初步数据和已知的 Hippo 功能，我们追求 Hippo 信号对于 VF 的发育、生长和维持至关重要 在 VF 损伤的情况下，YAP/TAZ-TEAD 信号的激活会导致纤维化。 当前的提议旨在揭示 YAP/TAZ-TEAD 的作用。 与 VF 成纤维细胞的纤维化反应和使用成纤维细胞形成喉组织的信号相关 从本研究中获得的数据将提供培养模型、大鼠室颤损伤模型和基因修饰小鼠。 为未来临床试验中研究的新治疗方法的开发奠定了基础。