紫背天葵激活UBA1调控Nrf2-Keap1泛素化的皮肤光损伤防护机制研究

紫外线辐射是导致皮肤光损伤、光老化甚至皮肤肿瘤的重要因素，目前尚缺乏有效防护药物。文献提示本病谱属祖国医学“日晒疮”范畴，应“从热论治”。我们发现清热解毒药紫背天葵可通过抗氧化发挥光防护作用，且与激动Nrf2相关，后者受Nrf2-Keap1泛素化影响，但具体机制不明。前期发现肝癌氧化应激中，泛素修饰激活酶1（UBA1）与Nrf2呈正相关，UBA1敲除显著下调Nrf2，而紫外线辐射下，紫背天葵可激活UBA1及Nrf2。因此，我们提出假说：紫背天葵激活UBA1，调控Nrf2-Keap1泛素化，促进Nrf2入核及其下游抗氧化基因表达，以祛除“光毒热之邪”，缓解皮肤光损伤。项目拟通过UVB诱导的动物和细胞模型，研究UBA1促进Nrf2 K63泛素化并入核，及紫背天葵激活UBA1调控Nrf2-Keap1泛素化的光防护机制，旨在为皮肤光损伤机制探索新的研究视角，为中医药防治光线性皮肤病提供客观科学依据

Ultraviolet radiation is an important factor leading to skin photodamage, photoaging and even skin tumors. There are no effective protective drugs at present.Literature suggests that the disease spectrum belongs to the category of “sunburnin” Traditional Chinese Medicine and should be “treated from heat”.We found that the antipyretic and antidote drug——Gynura bicolor DC(GB) had photoprotective effects through antioxidant activity, and was related to the activation of Nrf2, which is affected by Nrf2-Keap1 ubiquitination,while the specific mechanism is unclear.It was previously found that the ubiquitin-modified activating enzyme 1(UBA1) was positively correlated with Nrf2 in oxidative stress of liver cancer, and UBA1 knockout significantly inhibited the expression of Nrf2, while GB could activate UBA1 and Nrf2 under ultraviolet radiation.Therefore, we proposed a hypothesis,GB regulates Nrf2-Keap1 ubiquitination and promotes Nrf2 nuclear translocation,increases its downstream antioxidant gene expression by activating UBA1, so as to eliminate the "light toxin and heat" and alleviate skin photo-damage.Based on animal and cell models,the project intends to study the mechanism of UBA1 promoting the ubiquitination of Nrf2 K63 and nuclear translocation,and photo-protective mechanism of GB regulating the ubiquitination of Nrf2-Keap1 by activating UBA1, aiming to explore a new research perspective for the mechanism of skin photo-damage and provide an objective scientific basis for the prevention and treatment of skin photo-damage diseases by Traditional Chinese Medicine.