Neogenin Signalling during Hypoxia, Inflammation and Ischemia-Reperfusion

对于患有休克、败血症或急性器官衰竭的患者，治疗方案很少，而且价格昂贵。这些疾病的一个特征是炎症细胞浸润到受影响的组织中。最近的工作已经确定了最初在神经系统外轴突迁移过程中描述的内源性引导线索，并发现了它们的抗炎潜力。新生素受体是轴突生长过程中神经元引导蛋白的重要靶受体。在一系列实验中，我们能够证明neogenin显著影响白细胞迁移，并且具有neogenin （neogenin -/-）基因靶向抑制的动物显示炎症性器官损伤减少。在此，我们建议进一步定义新生素的调控及其在屏障功能降低和白细胞浸润相关条件下的功能影响。我们将研究neogenin在体外通过强迫过表达和抑制的作用。在体内，我们将在急性腹膜炎模型中研究neogenin对不同白细胞浸润的影响。采用全身缺氧和心肌IR损伤模型，研究新生素对血管渗漏和缺血组织损伤的作用。我们的目标是利用嵌合动物阐明新基因素信号传导的下游机制，并以此定义新基因素在神经系统之外的作用。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。

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.