Neogenin Signalling during Hypoxia, Inflammation and Ischemia-Reperfusion

对休克、败血症或急性器官衰竭患者的治疗选择很少，也很昂贵。这些情况的一个特点是炎症细胞渗透到受影响的组织中。最近的工作已经确定了最初在轴突迁移到神经系统之外时描述的内源性指导线索，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导向蛋白的重要靶向受体。在一系列实验中，我们能够证明新生素显着影响白细胞的迁移，并且具有新生素基因靶向抑制(新生素-/-)的动物显示出炎症器官损伤的减少。在此，我们建议进一步定义新生素的调节及其在屏障功能降低和白细胞渗透相关条件下的功能影响。我们将在体外通过强迫过度表达和抑制来研究新生素的作用。在体内，我们将研究新生素对急性腹膜炎模型中差异白细胞浸润的影响。采用全身缺氧和心肌缺血再灌注损伤模型，研究新生素在血管渗漏和缺血组织损伤中的作用。我们的目标是利用嵌合动物阐明新生素信号的下游机制，并因此定义新生素在神经系统之外的作用。因此，这项拨款建议将使人们更好地理解神经和免疫系统共有的基本生物学原理。

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.