HuR-Wisp1 signaling in cardiac fibroblasts

摘要 静止期细胞表型活化影响心肌纤维化的发生和调节 心脏成纤维细胞(CFs)向活性肌成纤维细胞(MFS)转化。这两种不同的细胞类型在 维持心脏细胞外基质(ECM)重构和收缩功能的动态平衡。 我们实验室的初步数据表明，HUR是体外激活CF-to-MF所必需的，并被鉴定 Wisp1是一个依赖于HUR的基因，能够独立地诱导MF活性。 这项建议的目的是确定Hur-Wisp1信号在病理过程中的体内作用。 心脏重塑和靶向HUR和/或Wisp1作为介导心脏重构的手段的可能性 活跃的Mf表型。我们假设心脏成纤维细胞中的Hur-Wisp1信号是必不可少的 肌成纤维细胞活性和促进体内病理性心脏重塑。AIM 1将使用新的鼠标型号 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性心脏重塑期间。然后，目标2将确定功能和 依赖于HUR的Wisp1表达调控在MF活性的启动和分解中的机制作用。 总体而言，这项工作将增强我们对Hur-Wisp1信号在 成纤维细胞在病理性心脏重塑中的作用并指导未来的治疗操作 HUR或HUR依赖性基因在心脏重构中的表达。

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.