HuR-Wisp1 signaling in cardiac fibroblasts

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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.