TGF-β/Nur77 Crosstalk在腹主动脉瘤中的作用和机制研究

It is the key problem to search for effective drug targets, early diagnosis, alleviated and reversal of the expansion of abdominal aneurysm. The applicant focused on aneurysms and vascular remodeling, and found that TGF- beta may be the key pathogenic factor in the formation of aneurysms. Our analysis by microarray bioinformatics and preliminary experiments found the crosstalk between orphan nuclear receptor Nur77 and TGF- beta: the expression of TGF- beta can activate Nur77, Nur77 can inhibit the expression of TGF- beta target gene at the transcriptional level, but the long-term sustained TGF-beta stimulation will lead to the weakening of the negative feedback function. Our results showed that the Nur77 agonist significantly alleviated the abdominal aortic aneurysm. But the relationship between AAA and crosstalk of Nur77/TGF- beta is not clear. This project will establish different animal models to clarify the mechanism of TGF- beta /Nur77 in abdominal aortic aneurysm and the detailed molecular network of Nur77 regulation. This research will provide the experimental evidence in order to elucidate the pathogenesis of abdominal aortic aneurysm, and provide a new target for the treatment of abdominal aortic aneurysm.

寻找有效的药物靶点，早期诊断、及时遏制和逆转腹动脉瘤（AAA）的扩张及破裂是目前研究的重点和难点。申报者长期致力于动脉瘤和血管重构的研究，发现TGF-β可能是贯穿AAA形成的核心致病分子。我们通过AAA组织芯片生物信息学分析发现孤儿核受体Nur77在AAA形成的中期明显升高，且给予Nur77激动剂可明显减轻腹主动脉瘤病变。进一步的预实验证实TGF-β与孤儿核受体Nur77之间存在复杂的Crosstalk关系：TGF-β能激活Nur77的表达，Nur77能在转录水平抑制TGF-β靶基因的表达，但是长期持续的TGF-β刺激会导致此负反馈作用减弱。但AAA不同阶段、不同细胞中Nur77/TGF-β Crosstalk机制尚不明确。本项目将构建不同模式动物，系统探讨TGF-β/Nur77 Crosstalk 参与AAA病变的作用及其详尽分子机制，为完善AAA的治疗策略提供新的理论依据。

本项目集中研究TGF-β/Nur77 Crosstalk参与夹层动脉瘤病变的作用及其机制。对临床及动物模型标本测序、建库及分析，通过生物信息学相关手段探讨参与夹层动脉瘤病变的不同细胞中（包括炎症细胞、血管平滑肌细胞、内皮细胞及成纤维细胞）TGF-β/Nur77 Crosstalk 在病变过程中的动态变化情况，找到其相关功能和作用机制，进而通过干预Nur77及TGF-β信号通路以恢复病变部位TGF-β信号通路的稳态，探讨治疗及预防动脉瘤夹层的新策略与新方法。