The fibrogenic role of Hippo-Yap signaling following ischemic injury

项目总结/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。以下 缺血性损伤，延长的肌成纤维细胞活化可导致加剧的细胞外基质产生， 心脏顺应性降低、肌细胞解偶联和进行性心力衰竭。然而，一个新兴的角色 关于心脏再生愈合的肌成纤维细胞的研究一直没有得到充分的重视和探索。 因此，人们对评估肌成纤维细胞在缺血性损伤后成人心脏中的作用非常感兴趣， 可以靶向控制肌成纤维细胞活化和失活的分子途径。在最近 我们发表的一项研究发现，在再生斑马鱼模型中，雅普基因的缺失会加剧疤痕 形成，调节免疫细胞浸润和延迟心脏冷冻损伤后的心脏再生。 雅普是一种转录激活因子，可促进细胞存活和增殖，而Hippo则可抑制这种活性 信号通路通过Lats介导的磷酸化。最近有报道称， 雅普的表达或核心Hippo激酶的缺失延长了心肌细胞的再生窗口， 因此，治疗靶向Hippo-Yap通路是一种有前途的方法， 心脏的肌肉再生然而，了解雅普活性在心肌细胞中的作用， 在实施靶向该途径的治疗性再生方法之前，再生是至关重要的。在这里， 我们的初步数据显示，雅普对再生斑马鱼的瘢痕形成和消退至关重要 心脏和哺乳动物心脏成纤维细胞中雅普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，精确调节肌成纤维细胞的反应， 靶向Hippo-Yap通路将促进关键伤口愈合和促再生反应， 防止缺血性损伤后心脏中ECM的过度产生和纤维化。因此，本提案 目的是确定成年小鼠心脏损伤后Hippo-Yap信号在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.