PDF(Pubmed)
Abstract：
UNASSIGNED: The Rho-associated protein kinase and myosin light chain kinase (ROCK/MYLK) pathway undeniably plays a pivotal role in the pathophysiology of primary open-angle glaucoma (POAG). In our study, we utilized both ocular hypertension (OHT) rabbit models and clinical investigations to gain invaluable insights that propel the development of novel treatments targeting proteins and genes associated with the trabecular meshwork (TM), thereby offering promising avenues for the management of POAG.
UNASSIGNED: Following microbead injections into the anterior chamber of the ocular cavity of rabbits, we observed elevated histiocyte numbers and immune scores for MYLK-4/ pMLC-2, alongside a reduction in the void space within the TM. Notably, treatment was performed with 0.1% ITRI-E-(S)-4046, a compound with dual kinase inhibitor (highly specific inhibitor of ROCK1/2 and MYLK4), significantly reduced intraocular pressure (IOP; P < 0.05) and expanded the void space within the TM (P < 0.0001) compared with OHT rabbits. In clinical investigations, we utilized whole transcriptome sequencing to analyze gene expression specifically related to the TM, obtained from patients (5 early-onset and 5 late-onset) undergoing trabeculectomy.
UNASSIGNED: Our findings revealed 103 differential expression genes (DEGs) out of 265 molecules associated with the Rho family GTPase pathway, exhibiting a P value of 1.25E-10 and a z-score of -2.524. These results underscore significant differences between the early-onset and late-onset POAG and highlight the involvement of the ROCK/MYLK pathway.
UNASSIGNED: These findings underscore the critical involvement of the ROCK/MYLK pathway in both OHT-related and different onsets of POAG, providing valuable insights into the TM-related molecular mechanisms underlying the disease.
UNASSIGNED: Following microbead injections into the anterior chamber of the ocular cavity of rabbits, we observed elevated histiocyte numbers and immune scores for MYLK-4/ pMLC-2, alongside a reduction in the void space within the TM. Notably, treatment was performed with 0.1% ITRI-E-(S)-4046, a compound with dual kinase inhibitor (highly specific inhibitor of ROCK1/2 and MYLK4), significantly reduced intraocular pressure (IOP; P < 0.05) and expanded the void space within the TM (P < 0.0001) compared with OHT rabbits. In clinical investigations, we utilized whole transcriptome sequencing to analyze gene expression specifically related to the TM, obtained from patients (5 early-onset and 5 late-onset) undergoing trabeculectomy.
UNASSIGNED: Our findings revealed 103 differential expression genes (DEGs) out of 265 molecules associated with the Rho family GTPase pathway, exhibiting a P value of 1.25E-10 and a z-score of -2.524. These results underscore significant differences between the early-onset and late-onset POAG and highlight the involvement of the ROCK/MYLK pathway.
UNASSIGNED: These findings underscore the critical involvement of the ROCK/MYLK pathway in both OHT-related and different onsets of POAG, providing valuable insights into the TM-related molecular mechanisms underlying the disease.
摘要：
Rho相关蛋白激酶和肌球蛋白轻链激酶（ROCK/MYLK）途径无疑在原发性开角型青光眼（POAG）的病理生理中起着关键作用。在我们的研究中,我们利用高眼压（OHT）兔模型和临床研究获得了宝贵的见解，推动了针对与小梁网（TM）相关的蛋白质和基因的新型治疗方法的发展。从而为POAG的管理提供了有希望的途径。
■将微珠注射入兔子眼腔前房后，我们观察到MYLK-4/pMLC-2的组织细胞数量和免疫评分升高，同时TM内的空隙空间减少。值得注意的是,用0.1%ITRI-E-(S)-4046进行治疗，该化合物具有双重激酶抑制剂（ROCK1/2和MYLK4的高特异性抑制剂），与OHT兔相比，显着降低眼压（IOP；P<0.05）并扩大TM内的空隙空间（P<0.0001）。在临床调查中，我们利用全转录组测序来分析与TM特异性相关的基因表达，从接受小梁切除术的患者（5例早发性和5例晚发性）获得。
■我们的发现揭示了与Rho家族GTPase途径相关的265个分子中的103个差异表达基因(DEGs)，表现出1.25E-10的P值和-2.524的z分数。这些结果强调了早发性和晚发性POAG之间的显着差异，并强调了ROCK/MYLK途径的参与。
■这些发现强调了ROCK/MYLK通路在POAG的OHT相关和不同发病中的关键参与，为潜在的TM相关分子机制提供有价值的见解。
■将微珠注射入兔子眼腔前房后，我们观察到MYLK-4/pMLC-2的组织细胞数量和免疫评分升高，同时TM内的空隙空间减少。值得注意的是,用0.1%ITRI-E-(S)-4046进行治疗，该化合物具有双重激酶抑制剂（ROCK1/2和MYLK4的高特异性抑制剂），与OHT兔相比，显着降低眼压（IOP；P<0.05）并扩大TM内的空隙空间（P<0.0001）。在临床调查中，我们利用全转录组测序来分析与TM特异性相关的基因表达，从接受小梁切除术的患者（5例早发性和5例晚发性）获得。
■我们的发现揭示了与Rho家族GTPase途径相关的265个分子中的103个差异表达基因(DEGs)，表现出1.25E-10的P值和-2.524的z分数。这些结果强调了早发性和晚发性POAG之间的显着差异，并强调了ROCK/MYLK途径的参与。
■这些发现强调了ROCK/MYLK通路在POAG的OHT相关和不同发病中的关键参与，为潜在的TM相关分子机制提供有价值的见解。
