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 心脏纤维化的发展和调节受静止的表型激活的影响 心脏成纤维细胞（CFS）至活性肌纤维细胞（MFS）。这两种不同的细胞类型在 维持心脏的细胞外基质（ECM）重塑和收缩功能的稳态。 来自我们实验室的初步数据表明，HUR是在体外激活CF至MF所必需的，并确定 WISP1是一个能够独立诱导MF活性的HUR依赖性基因。 该提案的目的是确定病理过程中HUR WISP1信号的体内作用 心脏重塑以及针对HUR和/或WISP1的潜力作为调解解决方案的一种手段 活性MF表型。我们假设心脏成纤维细胞中的hur-wisp1信号对于 肌纤维细胞活性并促进体内病理心脏重塑。 AIM 1将利用新的鼠标模型 由我们的CF和MF特定的HUR创建，以确定其在心脏成纤维细胞中的功能作用 在压力超负荷后的病理心脏重塑期间。 AIM 2然后将确定功能，并且 HUR依赖性控制WISP1表达对MF活性的启动和解决的机理作用。 总体而言，这项工作将增强我们对HUR WISP1信号的功能影响的理解 病理心脏重塑期间的成纤维细胞功能，并指导潜在的未来治疗操作 心脏重塑中的HUR或HUR依赖性基因表达。