The modulation of the hematopoietic system by Paraoxonase-2

人类酶对氧磷酶-2 （PON2）抵消，即水解某些细菌毒力因子，因此是先天免疫系统的一部分。此外，PON2是关键的细胞抗氧化酶之一。其减少氧化应激和对后续信号通路的影响是本项目范围的核心。由于PON2的功能，它被认为是细胞保护酶，在体内已被证明可以减轻动脉粥样硬化。研究潜在的机制，我们之前证明了PON2减少线粒体和内质网应激诱导的凋亡，从而产生抗凋亡作用，保护癌细胞免受化疗药物的细胞毒性作用。因此，PON2在许多肿瘤中被发现过表达，它的敲除会导致一些癌细胞死亡。同样，许多研究将PON2与患者的几种肿瘤联系起来。特别是在某些白血病中，PON2水平与分期、预后和治疗反应直接相关。就造血干细胞而言，这支持了自我更新和分化是由氧化还原敏感途径集中调节的概念。同时，我们发现PON2缺陷小鼠的造血室在数量和功能水平上都发生了显著的变化。在干细胞和祖细胞中，氧化还原信号的重要性最近得到了相当大的关注。然而，PON2的作用从未被分析过。因此，本项目的目标是揭示PON2通过氧化还原介导的途径控制干细胞和祖细胞的细胞周期调节、凋亡、分化和功能。这扩展到外周血细胞，特别是红细胞和应激诱导的红细胞生成。此外，我们希望在癌症和干细胞中确定PON2调节和被调节的信号通路。总之，我们的分子和体内研究有助于揭示与人类疾病明确相关的潜在促癌酶的关键功能。这为对氧磷酶的研究领域开辟了新的途径，并将氧化还原介导的事件与造血干细胞功能直接联系起来。

The human enzyme paraoxonase-2 (PON2) counteracts, i.e. hydrolyzes certain bacterial virulence factors and as such is part of the innate immune system. In addition, PON2 is among the critical cellular anti-oxidative enzymes. Its reduction of oxidative stress and impact on subsequent signaling pathways are central to the scope of this project. Due to its function, PON2 is regarded as cyto-protective enzyme and it has been shown to attenuate atherosclerosis in vivo. Studying underlying mechanisms, we previously demonstrated a reduction of mitochondrial and ER stress-induced apoptosis by PON2, resulting in an anti-apoptotic effect that protects cancer cells against cytotoxic effects of chemotherapeutics. In accordance, PON2 is found overexpressed in many tumors and its knock-down induces death of several cancer cells. Alike, many studies associated PON2 with several tumors in patients. Especially in certain leukemias, PON2 levels directly correlate with staging, outcome prognosis and therapy response. With respect to hematopoietic stem cells, this supports the concept that self-renewal and differentiation are centrally regulated by redox-sensitive pathways. Concordantly, we found significant alterations in the hematopoietic compartment of PON2 deficient mice, both at quantitative and functional levels.In stem and progenitor cells, the importance of redox-signaling recently gained considerable interest. However the role of PON2 has never been analyzed. Thus, the goal of this project is to reveal the redox-mediated pathways by which PON2 controls cell cycle regulation, apoptosis, differentiation and function of stem and progenitor cells. This is extended to peripheral blood cells, particularly erythrocytes and stress-induced erythropoiesis. Moreover, we want to identify both PON2 regulating and regulated signaling pathways in cancer and stem cells. Together, our molecular and in vivo studies help to uncover key functions of a potentially pro-oncogenic enzyme clearly relevant to human diseases. This opens new avenues to the Paraoxonase research field and directly links redox-mediated events with hematopoietic stem cell functions.