The fibrogenic role of Hippo-Yap signaling following ischemic injury

项目摘要/摘要 终末期心力衰竭是心肌梗死(MI)等心脏损伤的常见结局。跟随 缺血性损伤，长时间的肌成纤维细胞激活可导致细胞外基质产生加剧， 心脏顺应性降低，心肌细胞解偶联，进行性心力衰竭。然而，一个新兴的角色 对于心肌成纤维细胞关于心脏再生愈合的研究一直被低估和研究不足。 因此，评估肌成纤维细胞在成人心脏缺血损伤后的作用受到了极大的关注。 可靶向控制肌成纤维细胞激活和失活的分子途径。在最近 已发表的研究发现，在再生斑马鱼模型中YAP基因缺失会加剧瘢痕 形成，调节免疫细胞的渗透，延迟心脏冷冻损伤后的心脏再生。 YAP是一种转录激活剂，可促进被河马抑制的细胞存活和增殖 LATS介导的磷酸化信号通路。最近有报道称，要么强迫 YAP的表达或核心河马蛋白激酶的缺失延长了心肌细胞的再生窗口 因此，以河马-YAP通路为靶点的新生啮齿动物心脏是一种有希望的治疗方法 心脏的肌肉化。然而，了解非心肌细胞中YAP活性在心脏疾病中的作用 在实施针对这一途径的治疗性再生方法之前，再生是至关重要的。这里, 我们的初步数据显示，YAP对于再生斑马鱼的疤痕形成和分解是必不可少的。 心脏和哺乳动物心脏成纤维细胞中YAP的缺失调节纤维化和炎症 细胞/趋化因子基因程序。我们的中心理论是通过精确地调节肌成纤维细胞的反应 靶向河马-YAP通路将促进关键的伤口愈合和促再生反应，而 预防心脏缺血损伤后细胞外基质的过度产生和纤维化。因此，这项提议 目的明确Hippo-Yap信号在成年小鼠心脏损伤后肌成纤维细胞中的作用。

PROJECT SUMMARY/ABSTRACT End stage heart failure is a common outcome of cardiac injury such as myocardial infarction (MI). Following ischemic injury, prolonged myofibroblast activation can lead to exacerbated extracellular matrix production, decreased cardiac compliance, myocyte uncoupling, and progressive heart failure. However, an emerging role for myofibroblasts regarding cardiac regenerative healing has been underappreciated and underexplored. Thus, there is great interest in assessing myofibroblast's role in the adult heart following ischemic injury and molecular pathways that can be targeted to control myofibroblast activation and inactivation. In recently published studies we found that genetic deletion of Yap in the regenerative zebrafish model exacerbated scar formation, modulated immune cell infiltration, and delayed cardiac regeneration following cardiac cryoinjury. Yap is a transcriptional activator that promotes cell survival and proliferation that is inhibited by the Hippo signaling pathway through Lats mediated phosphorylation. It was recently reported that either forced expression of Yap, or the deletion of core Hippo kinases extend the regenerative window of cardiomyocytes in neonatal rodent hearts, thus, therapeutically targeting the Hippo-Yap pathway is a promising approach for remuscularization of the heart. However, understanding the role of Yap activity in non-myocytes during cardiac regeneration is critical prior to implementing therapeutic regenerative approaches targeting this pathway. Here, our preliminary data show that Yap is essential for scar formation and resolution in the regenerating zebrafish heart and depletion of Yap in mammalian cardiac fibroblasts modulates fibrotic and inflammatory cyto/chemokine gene programs. Our central theory is that precisely modulating the myofibroblast response by targeting the Hippo-Yap pathway will facilitate critical wound healing and pro-regenerative responses while preventing excessive ECM production and fibrosis in the heart following ischemic injury. Thus, this proposal aims to define the role of Hippo-Yap signaling in myofibroblasts following cardiac injury in adult mice.