HuR-Wisp1 signaling in cardiac fibroblasts

心脏成纤维细胞中的 HuR-Wisp1 信号传导

• 批准号: 10751223
• 负责人: Sharon Parkins
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751223
• 关键词: Binding; Cardiac; Cardiac Myocytes; Data; Development; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Future; Gene Expression; Genes; Goals; Homeostasis; Hour; HuR protein; In Vitro; Mediating; Mediator; Mus; Myofibroblast; Pathologic; Phenotype; Play; Publishing; RNA-Binding Proteins; Recombinants; Regulation; Resolution; Role; Signal Transduction; Small Interfering RNA; Therapeutic; Transforming Growth Factor beta; Translations; Untranslated RNA; Up-Regulation; Variant; Work; cardioprotection; cell type; connective tissue growth factor; coronary fibrosis; heart function; heart preservation; in vitro activity; in vivo; knock-down; loss of function; mouse model; novel; overexpression; periostin; pharmacologic; pressure; response; therapeutic target

SUMMARY The development and regulation of cardiac fibrosis is influenced by the phenotypic activation of quiescent cardiac fibroblasts (CFs) to active myofibroblasts (MFs). These two distinct cell types play key roles in maintaining the homeostasis of extracellular matrix (ECM) remodeling and contractile functions of the heart. Preliminary data from our lab demonstrates that HuR is necessary for CF-to-MF activation in vitro and identified Wisp1 as a HuR-dependent gene capable of independently inducing MF activity. The goal of this proposal is to determine the in vivo role of HuR-Wisp1 signaling during pathological cardiac remodeling and the potential for targeting HuR and/or Wisp1 as a means to mediate resolution of the active MF phenotype. We hypothesize that HuR-Wisp1 signaling in cardiac fibroblasts is essential for myofibroblast activity and promotes pathological cardiac remodeling in vivo. Aim 1 will utilize new mouse models created by our with a CF and MF-specific deletion of HuR to determine its functional role in cardiac fibroblasts during pathological cardiac remodeling following pressure overload. Aim 2 will then identify the functional and mechanistic role of HuR-dependent control of Wisp1 expression on the initiation and resolution of MF activity. Overall, this work will enhance our understanding of the functional impact of HuR-Wisp1 signaling on fibroblast function during pathological cardiac remodeling and guide potential future therapeutic manipulation of HuR or HuR-dependent gene expression in cardiac remodeling.

概括 心脏纤维化的发生和调节受静止期细胞表型激活的影响 心脏成纤维细胞（CF）转变为活性肌成纤维细胞（MF）。这两种不同的细胞类型在 维持细胞外基质（ECM）重塑和心脏收缩功能的稳态。 我们实验室的初步数据表明，HuR 对于 CF 到 MF 的体外激活是必需的，并已鉴定 Wisp1 作为 HuR 依赖性基因，能够独立诱导 MF 活性。 本提案的目标是确定 HuR-Wisp1 信号传导在病理过程中的体内作用 心脏重塑以及靶向 HuR 和/或 Wisp1 作为介导解决问题的手段的潜力 活跃的 MF 表型。我们假设心脏成纤维细胞中的 HuR-Wisp1 信号对于 肌成纤维细胞活性并促进体内病理性心脏重塑。目标 1 将使用新的鼠标模型 由我们通过 CF 和 MF 特异性删除 HuR 来确定其在心脏成纤维细胞中的功能作用 压力超负荷后的病理性心脏重塑期间。然后目标 2 将确定功能和 HuR 依赖性 Wisp1 表达控制对 MF 活性启动和消退的机制作用。 总的来说，这项工作将增强我们对 HuR-Wisp1 信号传导对 病理性心脏重塑过程中成纤维细胞的功能并指导未来潜在的治疗操作 心脏重塑中的 HuR 或 HuR 依赖性基因表达。