The role of neutrophil YAP in cardiac ischemia/reperfusion inflammation and injury

中性粒细胞YAP在心肌缺血/再灌注炎症和损伤中的作用 学生：杰米·弗朗西斯科，M.S. 导师：多米尼克·德尔·雷博士。 摘要：心肌梗塞(MI)是世界范围内的头号死亡原因，声称 比三种最常见的癌症加起来还多。虽然再灌流目前是 心脏缺血性损伤的金标准治疗，它矛盾地恶化了心脏 结果通过增加炎症和细胞凋亡，进一步的心肌细胞损失和扩大 脑梗塞。尽管是心脏预后恶化的主要原因，但目前还没有可用的 对再灌注引起的这种继发性损伤的治疗，是对 心肌梗死的治疗。中性粒细胞是第一批被招募到心脏的炎性细胞 损伤及其数量已被证明与梗死灶大小呈正相关。虽然 中性粒细胞导致急性炎症和梗塞扩大，导致中性粒细胞耗尽。 心肌梗死后心脏修复功能受损。因此，对其作用机制的进一步探讨 需要特定的中性粒细胞功能来调节炎症和改善心脏预后 在再灌流期间。这项研究的长期目标是发现新的治疗靶点 促炎症中性粒细胞功能使炎症的靶向调节成为可能 不影响再灌流期间的修复。我们实验室和其他实验室之前的调查已经 河马途径下游效应蛋白YAP被鉴定为一种 缺血性心脏损伤后心脏结局的关键调节因子。来自我们的初步数据 新产生的中性粒细胞特异性Yap KO小鼠(Yap F//F：MRP8-cre)显示梗塞减少 急性加重期与对照组大小和炎症基因表达的比较 缺血/再灌流(I/R)。这些数据支持我们的假设，即中性粒细胞YAP是积极的 调节炎症，从而调节I/R后的心脏损伤。拟议的研究的目标是 目的：明确YAP在特定的促炎性中性粒细胞功能中的作用及随后的 对再灌注期心脏损伤的影响，以改善I/R损伤后的心功能。至 为此，我们提出了以下目标：1)确定心脏损伤和心肌梗死后 中性粒细胞特异性Yap KO小鼠的炎症状态，2)YAP的作用 再灌注期中性粒细胞功能的表达及其机制。 完成后，我们将阐明YAP在特定的中性粒细胞促炎中的作用。 心脏再灌流过程中的功能。此外，我们相信这些研究将揭示新的 在不影响修复机制的情况下调节炎症的治疗靶点 心脏。由于再灌注造成的损伤目前还没有有效的治疗方法，因此 这项工作可能会推动这一领域朝着改善MI患者的治疗选择方向发展。

Title: The role of neutrophil YAP in cardiac ischemia/reperfusion inflammation and injury Student: Jamie Francisco, M.S. Mentor: Dr. Dominic Del Re, PhD. Abstract: Myocardial Infarction (MI) is the number one cause of death worldwide, claiming more lives than the three most prevalent cancers combined. While reperfusion is currently the gold standard treatment of ischemic injury in the heart, it paradoxically worsens cardiac outcomes by increasing inflammation and apoptosis, furthering myocyte loss and expanding the infarct. Despite being a major contributor to worsening cardiac outcomes, there are no available treatments for this secondary injury caused by reperfusion, presenting a major limitation in the treatment of MI. Neutrophils are among the first inflammatory cells recruited to the heart after injury and their numbers have been shown to positively correlate to infarct size. Although neutrophils contribute to acute inflammation and infarct expansion, neutrophil depletion results in defective cardiac repair after infarct. Therefore, further investigation into the mechanisms of specific neutrophil functions is needed to regulate inflammation and improve cardiac outcomes during reperfusion. The long-term goal of this research is to uncover novel therapeutic targets of proinflammatory neutrophil functions to make possible targeted modulation of inflammation without affecting repair during reperfusion. Previous investigations by our lab and others have identified Yes-Associated Protein (YAP), a downstream effector of the Hippo pathway, as a critical regulator of cardiac outcomes after ischemic heart injury. Preliminary data from our newly generated neutrophil-specific YAP KO mouse (YAP F//F: MRP8-cre) show decreased infarct size and inflammatory gene expression when compared to controls after acute ischemia/reperfusion (I/R). These data support our hypothesis that neutrophil YAP positively regulates inflammation and therefore, cardiac injury, after I/R. The goal of the proposed study is to define the role of YAP in specific pro-inflammatory neutrophil functions and the subsequent effect on cardiac injury during reperfusion to improve cardiac outcomes after I/R injury. To investigate this, we propose the following aims: 1) Determine cardiac injury and post infarct inflammatory status in neutrophil-specific YAP KO mice, 2) Determine the effect of YAP expression on neutrophil function during reperfusion and investigate the underlying mechanism. Upon completion, we will have elucidated the role of YAP in specific neutrophil proinflammatory functions during cardiac reperfusion. Furthermore, we believe these studies will reveal novel therapeutic targets for the modulation of inflammation without affecting the repair mechanism in the heart. As the injury due to reperfusion currently has no effective treatment, the results of this work could advance the field toward improved therapeutic options for MI patients.