Regulation of antioxidant gene expression, oxidative stress resistance and ageing by peroxiredoxins

我们的细胞不可避免地暴露于有害的活性氧（ROS），这些活性氧是作为正常代谢的不需要的副产物产生的。暴露于阳光，药物和环境化学物质，如重金属，也会导致细胞中ROS水平增加。ROS导致细胞损伤（氧化应激），这是衰老和许多疾病（如癌症）的重要原因。我们的细胞含有保护性抗氧化蛋白，可以解毒ROS，限制这种细胞损伤。氧化应激刺激抗氧化剂的产生增加。过氧化物还原酶是一组抗氧化蛋白，可防止氧化应激，并已被证明在癌症中发挥作用。过氧化物酶存在于不同的组织中，具有多种不同的活性。利用线虫线虫的遗传研究，我们将研究不同组织中的过氧化物酶如何防止氧化应激和衰老。这项工作还将确定增加抗氧化剂水平所需的基因，以应对氧化应激。秀丽隐杆线虫的遗传学研究对人类基本生物学过程的重要洞察力得到了广泛的认可。例如，最近有两项诺贝尔医学奖授予了通过对秀丽隐杆线虫的研究所取得的进展。除了它们的遗传顺从性之外，这些蠕虫还有许多特点，使它们非常适合我们的研究。例如，它们只有几周的短暂寿命将使我们能够快速确定我们识别的基因是否会影响衰老。事实上，我们将能够检查这些基因是否参与已知的寿命延长机制。重要的是，我们发现的基因极有可能在人类中具有对应物，这可能对预防癌症，细菌感染和与衰老相关的疾病很重要。最终，这些研究可能会建议未来的策略，以操纵氧化应激保护蛋白的水平，可用于预防衰老和年龄相关疾病。

Our cells are unavoidably exposed to harmful reactive oxygen species (ROS) which are produced as unwanted bi-products of normal metabolism. Exposure to sunlight, drugs and environmental chemicals, such as heavy metals, also lead to increased ROS-levels in cells. ROS cause cellular damage (oxidative stress) that is an important cause of ageing and of many diseases, such as cancer. Our cells contain protective antioxidant proteins which detoxify ROS, limiting this cellular damage. Oxidative stress stimulates the increased production of antioxidants. Peroxiredoxins are one such group of antioxidant proteins which protect against oxidative stress and have been shown to have roles in cancer. Peroxiredoxins are found in different tissues and have several different activities. Using genetic studies in the nematode worm Caenorhabditis elegans we will examine how peroxiredoxins in different tissues protect against oxidative stress and ageing. This work will also identify genes required for increasing antioxidant levels in response to oxidative stress. The power of genetic studies C.elegans to yield important insight into fundamental biological processes in humans is widely recognised. For example, two Nobel Prizes for Medicine have been recently awarded for advances made through studies in C.elegans. In addition to their genetic amenability, these worms have a number of features which make them ideally suited to our studies. For instance, their short lifespan of only a few weeks will allow us to rapidly determine whether genes we identify affect ageing. Indeed we will be able to examine whether these genes are involved in known lifespan-increasing mechanisms. Importantly, genes we identify are extremely likely to have counterparts in human which may be important in protecting against cancer, bacterial infections and ageing-associated diseases. Ultimately, these studies may suggest future strategies to manipulate levels of oxidative stress protective proteins that might be used to prevent ageing and age related diseases.