过载机械应力是椎间盘退变的主要启动因素，髓核纤维化是椎间盘退变性疾病(DDD)发展的关键环节，但过载机械应力促进髓核纤维化的分子机制尚不明确。本项目组前期研究发现髓核细胞胞浆中的心肌素相关转录因子-A(MRTF-A)在过载机械应力刺激下进入胞核，促进结缔组织生长因子(CTGF)和α-平滑肌肌动蛋白(α-SMA)等组织纤维化相关物质表达，而干预RhoA信号通路可抑制MRTF-A转入胞核。我们由此推论：过载机械应力通过激活髓核细胞的RhoA通路促使MRTF-A入核，进而增强CTGF和α-SMA的表达并导致髓核纤维化。本项目将在DDD病人原代髓核细胞中揭示过载机械应力诱导MRTF-A入核的分子机制，通过双后肢大鼠椎间盘退变模型明确RhoA通路抑制剂对DDD发病进程的阻抑作用，并在人离体椎间盘标本中进行验证，从而揭示RhoA/MRTF-A通路在DDD中的作用及分子机制，为靶向治疗DDD提供新思路。

Overloaded mechanical stress is the main factor in the initiation of intervertebral disc degeneration, while the development of nucleus pulposus fibrosis is a key indicator of the progress of degenerative disc disease (DDD). However, the molecular mechanism of nucleus pulposus fibrosis induced by mechanical stress is unclear. Our previous study found that myocardin related transcription factor-A (MRTF-A) enters the nucleus under overload mechanical stress in nucleus pulposus cells and promotes the expression of fibrosis-related factors such as connective tissue growth factor (CTGF) and alpha-smooth muscle actin (α-SMA). In addition, intervention of RhoA signaling pathway can significantly inhibit MRTF-A from entering nuclear and nucleus pulposus fibrosis. Therefore, we propose a ratiocination: overloaded mechanical stress promotes the nucleus localization of MRTF-A through activating RhoA signaling pathway, thus increasing CTGF and α-SMA expression and nucleus pulposus fibrosis. We will further reveal the molecular mechanism of overloaded mechanical stress mediated MRTF-A nuclear localization, then clarify the role of RhoA/MRTF-A signal pathway in promoting nucleus pulposus fibrosis in animal models, and then further study the role of the inhibitors of RhoA signaling pathway in the intervention of DDD pathogenesis，and finally verify the conclusions in the specimen of human intervertebral discs. This project will reveal the role and molecular mechanism of MRTF-A on nucleus pulposus fibrosis, and provide new ideas for targeted treatment of DDD.