Role of Netrin-4 during Myocardial Ischemia Reperfusion Injury

Netrin-4 在心肌缺血再灌注损伤中的作用

• 批准号: 494792295
• 负责人: Professor Dr. Peter Rosenberger
• 金额: --
• 依托单位: Klinik für Anaesthesiologie und Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/494792295?language=en
• 关键词: Role; Netrin; during; Myocardial; Ischemia

Myocardial ischemia reperfusion is the most prominent form of Ischemia-Reperfusion injury (IR) and is associated with significant mortality. During IR injury of the heart neutrophils infiltrate the affected areas, enhance tissue inflammation and as such increase tissue injury. Recent work by us has shown that not only the classical cytokine/ chemokine system guides leukocyte migration but also the system of neuronal guidance proteins. However, not much is known about the role of Netrin-4 (Ntn4) during myocardial IR injury. In preliminary experiments we found that genetic deletion of Ntn4 significantly alters neutrophil migration and that Ntn4 levels affect the extent of myocardial tissue injury following reperfusion. Therefore, we propose here in this project to decipher the role of Ntn4 during myocardial IR injury. We will investigate the role of Ntn4 tissue specific expression for immune cell recruitment, tissue inflammation and platelet-neutrophil complex formation. Next, we will use tissue specific deletion of Ntn4 in erythrocytes, endothelial cells, myocardial and lysozyme positive cells to identify the origin and impact of Ntn4 for myocardial tissue injury. This will provide novel evidence into the role of the Ntn4 during conditions associated with tissue inflammation and IR. Future therapies for myocardial IR injury and several other conditions associated with IR might be based on these findings.

心肌缺血再灌注是缺血-再灌注损伤（IR）的最主要形式，并与显著的死亡率相关。在心脏的IR损伤期间，中性粒细胞浸润受影响的区域，增强组织炎症并因此增加组织损伤。我们最近的工作表明，不仅经典的细胞因子/趋化因子系统引导白细胞迁移，而且神经元引导蛋白系统也可以引导白细胞迁移。然而，对Netrin-4（Ntn 4）在心肌IR损伤中的作用知之甚少。在初步实验中，我们发现Ntn 4的基因缺失显着改变中性粒细胞迁移，并且Ntn 4水平影响再灌注后心肌组织损伤的程度。因此，我们建议在这个项目中破译心肌缺血再灌注损伤过程中Ntn 4的作用。我们将研究Ntn 4组织特异性表达对免疫细胞募集、组织炎症和血小板-中性粒细胞复合物形成的作用。接下来，我们将使用红细胞、内皮细胞、心肌和溶菌酶阳性细胞中的组织特异性Ntn 4缺失来鉴定Ntn 4对心肌组织损伤的起源和影响。这将提供新的证据，在与组织炎症和IR相关的条件下的Ntn 4的作用。未来的治疗心肌IR损伤和其他几个条件与IR可能是基于这些研究结果。