PPARα和Nrf2共调控四氢生物蝶呤合成途径在放射性皮肤损伤防治中的作用和机制研究

Radiotherapy has gradually become an irreplaceable method for the treatment of various types of malignant tumors. Given that skin is the first tissue through which external radiation particles intrude during radiotherapy. Skin injury seems inevitableand will impact on patients significantly. However, the mechanism driving radiation-induced skin injury remains largely unknown and there is no effective countermeasures for this injury. Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide (NO) synthase. BH4 is essy to be oxidated and by irradiation-induced oxidative stress, leading to uncoupling of NOS. Guanosine 5′-triphosphate cyclohydrolase-1 (GTPCH-1) is a key limiting enzyme for BH4 synthesis. We predicted and found that NF-E2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptorα（PPARα）ameliorated radiation-induced skin injury. Our hypothesis is that radiation can induce theoxidation of BH4, which crippled the function of NOS and modulated radiation-induced skin injury. In this project, we will investigate the role of BH4 pathway on the pathogenesis of radiation-induced skin injury. Moreover, we will explore the mechanism of the transcritional regulation of Nrf2 and PPARα in the genenration of BH4. This project is likely to provide a new mechanism to illustrateradiation-induced skin injury and approach for the treatment of this disease.

电离辐射引起皮肤损伤的机理不明也缺乏有效的防治手段。四氢生物蝶呤（BH4）是一氧化氮合酶（NOS）等的重要辅助因子。BH4具有还原性，极易在受到电离辐射时被氧化失活，造成NOS解偶联加重病理损伤。生物信息学分析表明，BH4合成途径中的关键限速酶GTPCH1启动子上游含有Nrf2和PPARα结合位点。我们发现Nrf2和PPARα均可促进GTPCH1的表达并缓解电离辐射引起的皮肤细胞的损伤，但具体机制不详。本项目的科学假设为：电离辐射后BH4氧化失活，造成NOS解偶联；Nrf2和PPARα启动GTPCH1的生成，补充BH4，缓解辐射皮肤损伤。本项目拟通过多种分子生物学手段揭示BH4合成途径在放射性皮肤损伤防治中的作用；探索Nrf2及PPARα对BH4合成途径的关键酶的调控作用及机制；并进一步在动物模型中进行验证。本项目有望揭示电离辐射皮肤损伤发生发展的新机制，为防护和治疗提供新的方法。

电离辐射引起皮肤损伤的机理不明也缺乏有效的防治手段。四氢生物蝶呤（BH4）是一氧化氮合酶（NOS）等的重要辅助因子。BH4具有还原性，极易在受到电离辐射时被氧化失活，造成NOS解偶联加重病理损伤。生物信息学分析表明，BH4合成途径中的关键限速酶GTPCH1启动子上游含有Nrf2和PPARα结合位点。我们发现Nrf2和PPARα均可促进GTPCH1的表达并缓解电离辐射引起的皮肤细胞的损伤。本项目通过多种分子生物学手段揭示了BH4合成途径在放射性皮肤损伤防治中的作用；同时明确了Nrf2及PPARα对BH4合成途径的关键酶GTPCH1的调控作用及机制；Nrf2和PPARα能够直接靶向调控BH4合成途径中的关键限速酶GTPCH1；并在动物模型中进行了验证。本项目揭示了电离辐射皮肤损伤发生发展的新机制，为防护和治疗提供新的方法。