Mitochondrial dysfunction and biogenesis in inflammation and sepsis

败血症是机体对感染的系统性炎症反应，是重症监护病房死亡的主要原因。最近的数据表明，部分由免疫系统成分介导的线粒体损伤是败血症期间组织的病理特征。我们假设线粒体的再生和氧化磷酸化的恢复可能会改善败血症的恢复。在这个项目中，我们将研究经脂多糖和干扰素-γ经典激活的骨髓源性小鼠巨噬细胞的线粒体功能障碍和生物发生。根据初步数据，我们预计由诱导型一氧化氮合酶产生的一氧化氮（NO）在这两个过程中发挥关键作用。我们将采用最先进的分子生物学、遗传学和药理学工具来定义NO的作用，阐明潜在的信号通路，并研究线粒体生物发生对巨噬细胞存活的影响。随着越来越多的主要人类病理与慢性低度炎症和线粒体功能障碍有关，这项工作具有广泛的（病理）生理和临床意义。

Sepsis is a systemic inflammatory response of the body to infection and represents the major cause of death in intensive care units. Recent data identified mitochondrial damage, mediated in part by components of the immune system, as a pathologic feature of tissues during sepsis. We hypothesise that regeneration of mitochondria and restoration of oxidative phosphorylation may improve recovery from sepsis. In this project we will study mitochondrial dysfunction and biogenesis in bone marrow-derived murine macrophages upon classical activation with lipopolysaccharide and interferon-γ. Based on preliminary data we expect nitric oxide (NO), produced by inducible nitric oxide synthase, to play a critical role in both of these processes. We will employ state-of-the-art molecular biology, genetic and pharmacological tools to define the role of NO, to elucidate underlying signalling pathways and to study the consequences of mitochondrial biogenesis for macrophage survival. As an increasing number of major human pathologies are being related to chronic low-grade inflammation and mitochondrial dysfunction the proposed work has broad (patho-)physiological and clinical implications.