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Neogenin Signalling during Hypoxia, Inflammation and Ischemia-Reperfusion

缺氧、炎症和缺血再灌注期间的 Neogenin 信号传导

基本信息

批准号：
191123657
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：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/191123657?language=en
关键词：
Neogenin Signalling during Hypoxia Inflammation

项目摘要

Treatment options for patients suffering from shock, sepsis or acute organ failure are sparse and expensive. A hallmark of these conditions is the infiltration of inflammatory cells into the affected tissues. Recent work has identified endogenous guidance cues that were originally described during axonal migration outside the nervous system and discovered their antiinflammatory potential. The neogenin receptor is an important target receptor of neuronal guidance proteins during axonal growth. In a series of experiments we were able to demonstrate that neogenin significantly influences leukocyte migration and that animals with gene targeted repression of neogenin (Neogenin-/-) demonstrate reduced inflammatory organ injury. We propose here to further define neogenin regulation and its functional impact during conditions associated with reduced barrier function and the infiltration of leukocytes. We will study the role of neogenin in-vitro through forced overexpression and repression. In-vivo, we will investigate the influence of neogenin on differential leukocyte infiltration in a model of acute peritonitis. Using a model of whole body hypoxia and myocardial IR injury, we will then study the role of neogenin on vascular leak and ischemic tissue injury. We aim to elucidate downstream mechanisms of neogenin signalling employing chimeric animals and as such define the role of neogenin beyond the nervous system. Therefore, this grant proposal will lead to a better understanding of basic biological principles shared by the nervous and the immune system.

休克、脓毒症或急性器官衰竭患者的治疗选择稀少且昂贵。这些病症的标志是炎性细胞浸润到受影响的组织中。最近的工作已经确定了内源性的指导线索，最初被描述在轴突迁移到神经系统外，并发现他们的潜在的。再生素受体是轴突生长过程中神经元导向蛋白的重要靶受体。在一系列实验中，我们能够证明再生蛋白显著影响白细胞迁移，并且具有再生蛋白的基因靶向抑制（再生蛋白-/-）的动物表现出减少的炎性器官损伤。我们建议在这里进一步定义再生蛋白的调节及其功能的影响，在条件相关的屏障功能降低和白细胞浸润。我们将通过强制过表达和抑制来研究再生蛋白在体外的作用。在体内，我们将研究再生蛋白对急性腹膜炎模型中不同白细胞浸润的影响。利用全身缺氧和心肌IR损伤的模型，我们将研究再生素在血管渗漏和缺血性组织损伤中的作用。我们的目标是阐明下游机制再生蛋白信号采用嵌合动物，并因此定义再生蛋白的作用超出神经系统。因此，这项拨款提案将导致更好地理解神经和免疫系统共享的基本生物学原理。