Mechanisms of oxidative DNA damage by endogenous substances

背景资料：在发达国家，只有大约一半的癌症病例可以用确实接触化学品或遗传易感性来解释。身体的病理过程可能参与另一半病例的启动。在高血压患者肾癌发病率的增加中，血压调节激素血管紧张素II和醛固酮水平的升高可能发挥了作用。到目前为止，我们已经发现这两种化合物在体外以及在体内的肾脏中的遗传毒性作用。在上一个项目期间，我们可以明确地表明，遗传毒性效应是独立于血压。项目内容：负责增加血管紧张素II引起的氧化应激的酶将被确定。为了实现这一点，将使用缺乏产生NADPH氧化酶的超氧化物或过氧化氢的另一种同种型的动物。在我们获得第一个结果的同种型4的情况下，除了整体敲除动物外，还需要研究诱导型敲除模型，因为整体敲除已经显示出DNA损伤和肾功能受损，而无需血管紧张素II治疗。此外，将彻底研究血管紧张素II对细胞抗氧化防御的激活作用。这将提供一个洞察防御系统的诱导可能产生的有益影响。目标：在这最后一个项目部分的过程中，氧化应激源的识别和抗氧化防御的分析应该提供两个可能的目标，为药理学干预，以减少血管紧张素II引起的DNA损伤。首先将测试抗氧化防御的激活剂。

Background: Only approximately half of the cancer cases in developed countries can be explained by an assured exposition to chemicals or by a genetic predisposition. Pathological processes of the body could be involved in the initiation of the other half of the cases. In the increase of the kidney cancer incidence of hypertensive individuals, raised levels of the blood pressure-regulating hormones angiotensin II and aldosterone might play a role. Up to now we have found genotoxic effects of these two compounds in vitro as well as in vivo in the kidney. During the last project period we could definitely show that the genotoxic effects are independent from blood pressure.Project content: The enzyme responsible for the increased oxidative stress caused by angiotensin II will be identified. To achieve this, animals will be utilized which lack each another isoform of the superoxide or hydrogen peroxide producing NADPH oxidase. In the case of the isoform 4, where we obtained first results, besides the global knockout animal an inducible knockout model needs to be studied, since the global knockout already showed DNA damage and impaired kidney function without angiotensin II treatment. Additionally, the activation of the cellular antioxidative defense by angiotensin II will be thoroughly studied. This will provide an insight on the possible beneficial effects of an induction of the defense system.Goal: In the course of this last project part, the identification of the source of the oxidative stress and the analysis of the antioxidative defense are supposed to provide two possible targets for a pharmacological intervention to reduce DNA damage caused by angiotensin II. First activators of the antioxidative defense will be tested.