WISP-1调控Hedgehog-Gli1信号通路在黄韧带增生纤维化中的作用及机制研究

Hypertrophy of the ligamentum flavum(LF) is considered as a major contributor to the development of lumbar spinal canal stenosis(LSCS). Fibrosis is a main cause of LF hypertrophy, however, its precise molecular mechanism remains unknown. WISP-1 plays important roles in multiple organ fibrosis. Our previous studies have found that the abnormal expression of WISP-1 was associated with LF fibrosis, but its mechanism has not yet been elucidated. Our preliminary experiments found that the activation and abnormal expression of Hedgehog-Gli1 signaling pathway played an important role in LF fibrosis. Further study has showed that WISP-1 could activate the Hedgehog-Gli1 signaling in the LF cells. On this background, we hypothesize that WISP-1 regulates Hedgehog-Gli1 signaling, which is involved in the development and progression of LF fibrosis and hypertrophy. Therefore, we prepare to explore the specific role and mechanism of WISP-1 regulating Hedgehog-Gli1 signaling pathway in LF fibrosis in not only tissue, cellular and molecular levels but also animal models, and aim to elucidate whether WISP-1/Hedgehog-Gli1 signaling pathway is a key mechanism for the LF fibrosis. If successful, these studies will provide increase access to the pathological mechanism of LF fibrosis and offer a solid theoretical basis for future research to develop effective and safe therapy for LSCS.

黄韧带增生肥厚是导致腰椎管狭窄症的重要病因，纤维化是其主要病理变化，但确切机制不清。WISP-1在多器官纤维化中发挥重要作用，我们前期发现WISP-1异常表达与黄韧带纤维化相关，但机制未明。课题组通过分析比较肥厚黄韧带组织基因表达谱，发现Hedgehog-Gli1信号通路的活化及异常表达。进一步研究发现WISP-1能激活黄韧带细胞内Hedgehog-Gli1信号通路。本项目科学假说：WISP-1调控Hedgehog-Gli1信号通路参与黄韧带增生纤维化。基于此，本研究拟从临床标本、细胞分子水平结合动物模型在体实验，重点探讨WISP-1调控Hedgehog-Gli1信号通路在黄韧带纤维化中的作用及机制，以评估WISP-1/Hedgehog-Gli1信号通路是否为黄韧带纤维化的关键机制。此研究将使我们进一步加深对黄韧带纤维化病理机制的认识，并将为研发有效及安全的治疗手段提供夯实的理论基础。

黄韧带肥厚纤维化是导致腰椎管狭窄症的重要病因，我们前期发现WISP-1异常表达与黄韧带纤维化相关，但是其具体的机制不清楚。课题组发现肥厚黄韧带中Hedgehog-Gli1信号通路的活化及异常表达与黄韧带纤维化密切相关；体外实验发现机械应力能促进黄韧带细胞WISP-1的表达。进一步研究发现WISP-1能激活黄韧带细胞内Hedgehog-Gli1信号通路；另外，WISP-1通过调控Hedgehog-Gli1信号通路促进黄韧带成纤维细胞向肌成纤维细胞转换，导致胶原堆积，进而促进黄韧带增生纤维化。动物模型在体实验进一步证实肥厚黄韧带中存在WISP-1、Gli1和α-SMA的异常表达，Hedgehog-Gli1信号阻断剂Cyclopamine能减弱机械应力诱导的黄韧带增生纤维化。本研究揭示机械应力/WISP-1/Hedgehog-Gli1信号轴在黄韧带增生纤维化中起关键作用，此研究结果将使我们进一步加深对黄韧带纤维化病理机制的认识，并将为研发有效及安全的治疗手段提供夯实的理论基础。