Functional interplay of transcriptional activators in the regulation of the cytoprotective human CYP2J2 gene

人细胞色素P450 2J2（CYP 2J2）在许多组织中表达。这种酶作用于多不饱和脂肪酸，形成环氧化物，控制离子流，血管和炎症的大小，也帮助细胞在缺氧和其他压力的破坏性影响中生存下来。因此，CYP2J2在正常细胞和受损细胞中都具有重要作用。增加细胞中CYP2J2的量可能在防御损伤方面非常有价值。然而，直到最近，还没有治疗方法能够做到这一点，但我们现在知道，生物学上重要的维生素A衍生物全反式维甲酸（ATRA）可以增加细胞中的CYP2J2。在这个项目中，我们将建立在这一新发现的基础上，开发增加组织中CYP2J2的治疗方法。大约10%的人有一个变异的CYP2J2基因，与普通形式有一个核苷酸的不同。这种多态性变体可以降低CYP2J2酶的量并增加心血管风险。我们发现这种多态性位于基因的关键控制区，影响基因对转录因子的反应。本项目将详细研究CYP2J2基因及其天然变体通过与该控制区结合的转录因子的调节。我们还将测试该基因的多态性版本如何对应激刺激和增加细胞中野生型基因数量的ATRA等治疗作出反应。研究人类基因调控是困难的，因为我们不能轻易地测量它们在个体中的水平。因此，我们将制造转基因小鼠来研究人类CYP2J2的调节，并将测试我们在细胞中设计的治疗方法是否也在体内有效。这些研究将帮助我们设计药理学策略来增加细胞中的CYP2J2。通过维持CYP2J2的有益作用，并了解这些在变体中如何改变，该项目的一个重要成果可能是心血管疾病的新治疗方法。

Human cytochrome P450 2J2 (CYP2J2) is expressed in many tissues. This enzyme acts on polyunsaturated fatty acids to form epoxides that control ion fluxes, the size of blood vessels and inflammation, and also help cells to survive the damaging effects of oxygen deprivation and other stresses. So CYP2J2 has an important role in both normal and injured cells. Increasing the amount of CYP2J2 in cells may be extremely valuable in the defence against injury. Until recently, however, no treatments have been able to do this but we now know that the biologically important vitamin A derivative all-trans-retinoic acid (ATRA) can increase CYP2J2 in cells. In this project we will build on this novel finding to develop treatments that increase CYP2J2 in tissues. About 10% of people have a variant CYP2J2 gene that differs from the common form by one nucleotide. This polymorphic variant can decrease the amount of the CYP2J2 enzyme and increase cardiovascular risk. We ve found that this polymorphism is located in a critical control region of the gene and affects how the gene responds to transcription factors. The present project will study in detail the regulation of the CYP2J2 gene and its naturally occurring variant by transcription factors that bind to this control region. We will also test how the polymorphic version of the gene responds to stress stimuli and to treatments like ATRA that increase the amount of the wild-type gene in cells. Studying human gene regulation is difficult because we cannot easily measure their levels in individuals. So we will make transgenic mice to study human CYP2J2 regulation and will test whether the treatments we devise in cells also work in vivo. These studies will help us to design pharmacological strategies to increase CYP2J2 in cells. By maintaining the beneficial effects of CYP2J2, and understanding how these are altered in the variant, a significant outcome of the project could be a new treatment of cardiovascular disease.