Impact of the Plexin C1 - Semaphorin 7A axis during myocardial ischemia reperfusion injury

心肌缺血再灌注损伤过程中Plexin C1-Semaphorin 7A轴的影响

• 批准号: 225867371
• 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
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/225867371?language=en
• 关键词: Impact; Plexin; C1; Semaphorin; 7A

Ischemia reperfusion injury (IR) is a detrimental condition that affects a significant portion of patients in clinical medicine. Myocardial ischemia reperfusion is the most prominent form of IR injury and is associated with significant mortality. During IR injury 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. In the initial funding period of this project we were able to demonstrate that the guidance protein Semaphorin 7A (Sema7A) is induced during tissue hypoxia and that the guidance receptor Plexin C1 (PLXNC1) is involved into the control of acute inflammation. However, not much is known about the important interaction of the Sema7A PLXNC1 axis during myocardial IR injury. In preliminary experiments we found that genetic deletion of Sema7A significantly reduces the extent of myocardial tissue injury and that this effect seems to be mediated by PLXNC1. Therefore we propose here for the second funding period of this project to decipher the role of Sema7A PLXNC1 axis during myocardial IR injury. We will investigate the role of Sema7A PLXNC1 interaction and their tissue specific expression for leukocyte recruitment. Next, we will then use tissue specific deletion of Sema7A in erythrocytes, endothelial cells and lysozyme positive cells to identify the origin and impact of Sema7A for myocardial tissue injury. We will then also employ tissue specific deletion of PLXNC1 to describe its impact on leukocyte recruitment, tissue inflammation, platelet-neutrophil complex formation and the extent of myocardial IR injury. This will provide novel evidence into the role of the Sema7A PLXNC1 receptor ligand pair during conditions associated with leukocyte recruitment, tissue inflammation and IR. Future therapies for myocardial IR injury and several other conditions associated might be based on these findings.

缺血再灌注损伤（IR）是临床医学中影响相当一部分患者的有害疾病。心肌缺血再灌注是IR损伤的最主要形式，并且与显著的死亡率相关。在IR损伤期间，嗜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。在该项目的最初资助期间，我们能够证明组织缺氧期间诱导了导向蛋白Semaphorin 7A（Sema 7A），并且导向受体丛状蛋白C1（PLXNC 1）参与了急性炎症的控制。然而，还不太了解心肌IR损伤过程中Sema 7A PLXNC 1轴的重要相互作用。在初步的实验中，我们发现，Sema 7A基因缺失显着降低心肌组织损伤的程度，这种效果似乎是由PLXNC 1介导的。因此，我们建议在本项目的第二个资助期内破译Sema 7A PLXNC 1轴在心肌IR损伤中的作用。我们将研究Sema 7A PLXNC 1相互作用及其组织特异性表达对白细胞募集的作用。接下来，我们将使用红细胞、内皮细胞和溶菌酶阳性细胞中的Sema 7A的组织特异性缺失来鉴定Sema 7A对心肌组织损伤的起源和影响。然后，我们还将采用组织特异性缺失PLXNC 1来描述其对白细胞募集、组织炎症、血小板-中性粒细胞复合物形成和心肌IR损伤程度的影响。这将为Sema 7A PLXNC 1受体配体对在与白细胞募集、组织炎症和IR相关的疾病中的作用提供新的证据。未来针对心肌IR损伤和其他几种相关疾病的治疗可能会基于这些发现。