Alternate signalling pathways regulating the human arachidonate epoxygenase CYP2J2 in response to stress stimuli

缺氧或缺氧是由细胞供血减少引起的，是心血管系统（如中风、动脉粥样硬化）和许多其他器官（如癌症和化学介导的损伤）缺血性损伤的组成部分。现在已知，一组重要的蛋白质响应于缺氧而开启专门的靶基因，这组蛋白质是激活蛋白-1（AP-1）。我们已经发现，细胞色素P450 2 J2（CYP 2 J2），这是一种在细胞内形成有益脂肪酸产物的酶，在缺氧中减少，这是由于AP-1的活性增加。我们知道，类似的压力刺激也会导致CYP 2 J2的损失。同样，AP-1也参与其中，但我们有进一步的证据表明另一种途径的作用。该项目将探索这些途径如何单独和共同运作，以减少CYP 2 J2。研究人类基因的调控是困难的，因为我们不能轻易地监测它们在健康或患病个体细胞中的水平。因此，我们将建立转基因小鼠模型来研究人类CYP 2 J2的调控，这将为人类的情况提供信息。在这个项目中，我们将确定哪些因素关闭CYP 2 J2转基因，并将分析控制这种反应的细胞内的信号通路。这些研究的重要性在于，它们将帮助我们设计药理学策略，以防止受到压力的细胞中CYP 2 J2的丢失。这类药物可有效治疗中风和动脉粥样硬化中出现的缺血性损伤。如果我们能够维持CYP 2 J2水平，我们可能能够维持细胞中有益的脂肪酸水平，并有一种保持细胞存活的新治疗方法。

Hypoxia, or oxygen deprivation, is caused by the decreased supply of blood to cells and is a component of ischaemic injury to the cardiovascular system (e.g. stroke, atherosclerosis) and numerous other organs (e.g. cancer and chemical mediated injury). It is now known that an important group of proteins that switch on specialised target genes in response to hypoxia is Activator-Protein-1 (AP-1). We have found that cytochrome P450 2J2 (CYP2J2), which is an enzyme that forms beneficial fatty acid products inside cells, is decreased in hypoxia and that this is due to increased activity of AP-1. We know that similar stressful stimuli can also result in a loss of CYP2J2. Again, AP-1 is involved but we have further evidence for the role of another pathway. This project will explore how these pathways operate individually and together to decrease CYP2J2. Studying the regulation of human genes is difficult because we can not readily monitor their levels in cells in either healthy or sick individuals. So we will make transgenic mouse models to study human CYP2J2 regulation, which will provide information on the human situation. In this project we will identify which factors switch off the CYP2J2 transgene and will analyse the signalling pathways within cells that control this response. The importance of these studies is that they will help us to design pharmacological strategies to prevent the loss of CYP2J2 in cells that are stressed. Such agents may be effective in the treatment of ischaemic injury seen in stroke and atherosclerosis. If we can maintain CYP2J2 levels we may be able to maintain the beneficial fatty acid levels in cells and have a novel therapeutic approach for keeping cells alive.