生物力通过RhoA/Rock通路引起小梁网细胞向肌成纤维细胞转化

Glaucoma is the most common cause of irreversible blindness worldwide. The trabecular meshwork transformation and Extracellular Cell Matrix (ECM) deposition are believed the major reason of primary open angle glaucoma (POAG). The mechanisms underlying the pathological changes in the TM are not well understood. Several studies have shown that the short-term variations in IOP observed in glaucomatous populations are greater than those observed in normal populations. TM cells are pressure-sensitive cells that experience mechanical stress throughout their lifetime, but it how have an affect on the TM is not clear. Studies have confirmed RhoA/Rock signaling pathways involved in cytoskeleton reorganization, the extracellular matrix adjustment, inducing tissue fibrosis, and that can be activated by biological stress. We therefore speculated that large fluctuations in IOP that activated the RhoA/Rock signaling pathways, induced TM cells transformation, increased the TM density, resisted aqueous humor outflowing and were responsible for the ocular hypertension. To evaluate this hypothesis, we designed experiments to simulating the biomechanical stress which applied on TM tissue, detecting the RhoA/Rock pathways activity, TM cells transformation and the changes of ECM, clarify continuous biological stress produced by large intraocular pressure fluctuations could active Rho/Rock signaling pathways, inducing TM cells transformation and ECM accumulation, which were responsible for the pathogenesis of POAG. This study could provide the necessary condition of experimental study on POAG and preventative treatment for this disease.

青光眼是第一位不可逆致盲性疾病，在原发性开角型青光眼(POAG)中，小梁网细胞发生转化，细胞外基质(ECM)增多是主要致病原因，机制未知。POAG早期眼压波动比健康人群大得多。小梁网细胞是一种力学敏感型细胞，眼压波动产生的生物力，对小梁网产生怎样的影响还不明确。研究证实，RhoA/Rock参与细胞骨架重组、ECM调整，诱导组织纤维化，能够被生物力激活。我们前期实验证实眼压长时间大幅度波动能引起小梁网纤维化。因此推测，眼压波动产生的生物力，激活了RhoA/Rock通路，诱导小梁网细胞向肌成纤维细胞转化，生成ECM，导致眼压升高。本研究拟通过机械力模拟眼压波动产生的生物力，激活RhoA/Rock信号通路，检测小梁网细胞的转化及ECM的改变，阐明持眼压波动产生的生物力是激活小梁网细胞RhoA/Rock信号通路，引起小梁网细胞转化、ECM改变的最初诱因，为POAG的致病机理及早期预防提供理论基础。

青光眼是第一位不可逆致盲性疾病，在原发性开角型青光眼(POAG)中，小梁网细胞发生转化，细胞外基质(ECM)增多是主要致病原因，机制未知。POAG早期眼压波动比健康人群大得多。小梁网细胞是一种力学敏感型细胞，眼压波动产生的生物力，对小梁网产生怎样的影响还不明确。研究证实，RhoA/Rock参与细胞骨架重组、ECM调整，诱导组织纤维化，能够被生物力激活。我们前期实验证实眼压长时间大幅度波动能引起小梁网纤维化。在本研究中，我们首先通过蛋白质谱检测发现2D培养和3D培养的小梁网细胞之间有2954 个蛋白存在差异表达，p<0.05；其次，我们在2D培养的原代小梁网细胞中发现机械力拉伸促进细胞纤维化和凋亡。本研究进一步明确了机械力对小梁网细胞的损伤作用，并为2D培养和3D培养的小梁网细胞之间蛋白组学差异提供重要参考；为更好的调控体内生理环境下的小梁网细胞提供更多的作用靶点。