Neogenin Signalling during Hypoxia, Inflammation and Ischemia-Reperfusion

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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.