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

中性粒细胞YAP在心脏缺血/再灌注炎症和损伤中的作用

• 批准号: 10563123
• 负责人: Jamie Francisco
• 金额: $ 4.12万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10563123
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Apoptosis; Area; Blood Preservation; Blood flow; Calcium; Cardiac; Cardiac Myocytes; Cause of Death; Cells; Cessation of life; Clinical; Complement; Cytoplasmic Granules; Data; Doctor of Philosophy; Fibroblasts; Fibrosis; Gene Expression; Genetic Transcription; Goals; Granulopoiesis; Heart; Heart Injuries; Hour; In Vitro; Infarction; Infiltration; Inflammation; Inflammatory; Injury; Intervention; Investigation; Ischemia; Knockout Mice; Malignant Neoplasms; Medicine; Mentors; Mitochondria; Modeling; Molecular; Mus; Muscle Cells; Myeloid Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Outcome; Oxidative Stress; Pathologic; Pathway interactions; Patients; Pattern; Phagocytosis; Physiology; Production; Protein Inhibition; Proteins; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Research; Role; S100A8 gene; Signal Transduction; Signaling Protein; Students; Therapeutic; Work; acute stress; cardiac repair; cardioprotection; cofactor; comparison control; cytokine; effective therapy; extracellular; functional disability; heart cell; immune cell infiltrate; improved; in vivo; ischemic injury; neutrophil; new therapeutic target; novel; pharmacologic; protein activation; protein expression; recruit; repaired; response; standard care

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.

标题：中性粒细胞雅普在心肌缺血/再灌注炎症和损伤中的作用 学生：Jamie弗朗西斯科，理学硕士 导师：Dominic Del Re博士 摘要：心肌梗死（MI）是世界范围内的头号死亡原因， 比三种最常见的癌症加起来还要多虽然再灌注目前是 心脏缺血性损伤的金标准治疗，它矛盾地损害了心脏 结果增加炎症和凋亡，进一步肌细胞损失和扩大 梗塞尽管是心脏结局恶化的主要原因，但目前还没有可用的 这种由再灌注引起的继发性损伤的治疗，呈现出在治疗中的主要限制。 治疗MI。中性粒细胞是在心脏衰竭后最先募集到心脏的炎性细胞之一。 损伤和它们的数量已经显示与梗塞面积正相关。虽然 中性粒细胞导致急性炎症和梗死扩大，中性粒细胞耗竭导致 在梗死后心脏修复缺陷中的作用因此，进一步研究其作用机制， 需要特定的中性粒细胞功能来调节炎症和改善心脏结果 在再灌注期间。这项研究的长期目标是发现新的治疗靶点， 促炎性中性粒细胞的功能使炎症的靶向调节成为可能 而不影响再灌注期间的修复。我们实验室和其他人之前的研究 确定了是相关蛋白（雅普），Hippo途径的下游效应物，作为一种 缺血性心脏损伤后心脏结局的关键调节因子。我们的初步数据显示， 新产生的嗜中性粒细胞特异性雅普KO小鼠（雅普F//F：MRP 8-cre）显示梗死减少 与对照组相比， 缺血/再灌注（I/R）。这些数据支持我们的假设，中性粒细胞雅普阳性 调节I/R后的炎症和心脏损伤。拟议研究的目标是 明确雅普在特异性促炎中性粒细胞功能中的作用，以及随后的 对再灌注期间心脏损伤的影响，以改善I/R损伤后的心脏结局。到 为此，我们提出以下目的：1）确定心肌损伤和梗死后 2）确定雅普在嗜中性粒细胞特异性雅普KO小鼠中的作用， 表达对中性粒细胞功能的影响，并探讨其机制。 完成后，我们将阐明雅普在特异性中性粒细胞促炎症反应中的作用。 在心脏再灌注过程中发挥作用。此外，我们相信这些研究将揭示新的 调节炎症而不影响修复机制的治疗靶点 心脏由于再灌注损伤目前没有有效的治疗方法，因此， 这项工作可以推动该领域朝着改善心肌梗死患者的治疗选择方向发展。