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

点击翻译按钮获取中文摘要

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.