山玉兰根皮提取物衍生物靶向IKKβLeu303调控AEG-1抑制糖尿病肾病足细胞炎症反应的机制研究

糖尿病肾病（DN）治疗棘手，足细胞炎症反应在DN中作用关键、机制未明。在国家自然科学基金资助下，我们发现山玉兰根皮在自主研发的DN中药复方中作用至关重要，其根皮提取物衍生物MCL显著抑制DN足细胞炎症反应，很可能与结合IKKβ的Leu303位点调控星型细胞上调因子（AEG）-1有关，但确切机制待研究，且未见IKKβLeu303及AEG-1参与DN的报道。推测存在IKKβLeu303—IKKβ—AEG-1—IκBα新通路促进DN足细胞炎症反应，MCL靶向结合IKKβLeu303抑制该通路延缓DN进展。本项目拟应用电喷雾串联质谱分析、免疫共沉淀、超声微泡基因转移等方法，以IKKβLeu303为切入点，从体内外研究其介导IKKβ自我磷酸化，进而调控AEG-1促进IκBα磷酸化诱发DN足细胞炎症反应，并观察MCL对该过程的影响，以期揭示DN新的发病机制和干预靶点、阐明MCL治疗DN的确切分子机制。

Diabetic nephropathy (DN) is a knotty disease. Podocyte inflammation play a key role in the development of DN. However, the underlying mechanism is not very clear. Base on the National Natural Science Foundation of China, we found that the root bark of Magnolia delavayi is of vital importance in our herbal medicinal compound prescribe to the treatment of DN. The derivative of its extractive can significantly inhibit podocyte inflammation in DN , which may associates with leucine (Leu) 303 of IKKβ and astrocyte-elevated gene (AEG)-1, but the exact mechanism needs further study and there is no report about IKKβLeu303 and AEG-1 in DN. Thus, We speculate that there is a new pathway which is IKKβLeu303-IKKβ-AEG-1-IκBα contributing to podocyte inflammation in DN and MCL targets on IKKβLeu303 to inhibit this pathway and then delays the progress of DN. We will explore whether Leu303 mediates the autophosphorylation of IKKβ and then regulates AEG-1 to promote the phosphorylation of IκBα, leading to inflammation in podocyte of DN in vitro and in vivo mainly by electrospray tandem mass spectrometry, co-immunoprecipitation and ultrasound-mediated gene transfer, meanwhile, we will investigate the effect of MCL in this process. Our results are expected to reveal new pathogenesis of DN and a novel target spot for treatment of DN, and to clarify the exact molecular mechanism how MCL treats DN.