JAM-C通过抑制TAZ/KLF6通路来预防眼纤维化

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research Pub Date : 2025-05-19 DOI:10.1016/j.jare.2025.05.037

Min Chen, Wanhong Li, Yuxiang Du, Yuanlong Zhao, Ying Guo, Ying Li, Xiaolu Wang, Lijuan Huang, Xiaoling Zeng, Yihan Zhang, Guanqun Huang, Shasha Wang, Haiqing Kuang, Guangli Sun, Qin Jiang, Xuri Li, Weisi Lu

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引用次数: 0

摘要

眼纤维化是不可逆视力损害或失明的主要原因之一。目前，还没有针对这类疾病的有效药物。因此，了解潜在的机制是找到更好的治疗策略的先决条件。目的探讨关节黏附分子C （jamc）在眼纤维化中的作用。方法采用ELISA法检测眼纤维化患者玻璃体样品中JAM-C蛋白水平。通过构建Jam-c基因缺失小鼠和眼纤维化小鼠模型，研究Jam-c在体内的作用。通过sirna敲除JAM-C后，检测RPE细胞的EMT、增殖、迁移和凝胶收缩能力。通过RNA测序、co-IP、ChIP-qPCR和荧光素酶报告基因检测来研究潜在的机制。采用视网膜下注射腺相关病毒、免疫荧光、免疫印迹等方法，评价JAM-C在不同小鼠模型中预防眼纤维化的作用。结果在眼纤维化患者中，JAM-C表达明显降低。小鼠中Jam-c基因缺失加剧了眼纤维化，Jam-c基因敲低触发了RPE细胞的EMT过程。在机制上，我们发现JAM-C通过抑制TAZ的核定位和功能来抑制眼纤维化，TAZ通过与KLF6结合来促进其表达和活性，从而启动EMT级联。重要的是，aav介导的JAM-C增强减轻了不同小鼠模型的眼纤维化。结论本研究揭示了JAM-C通过抑制TAZ/KLF6通路预防眼部纤维化的新功能，为纤维化疾病的治疗提供了新的治疗可能性

本文章由计算机程序翻译，如有差异，请以英文原文为准。

JAM-C prevents ocular fibrosis by suppressing the TAZ/KLF6 pathway

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JAM-C prevents ocular fibrosis by suppressing the TAZ/KLF6 pathway

Introduction

Ocular fibrosis is one of the leading causes of irreversible visual impairment or blindness. Currently, there is no effective drug available for such diseases. Therefore, understanding the underlying mechanisms is a prerequisite for finding better therapeutic strategies.

Objectives

This study aims to investigate the role of the junctional adhesion molecule C (JAM-C) in ocular fibrosis.

Methods

The protein levels of JAM-C were determined in the vitreous humor samples of patients with ocular fibrosis using ELISA. Jam-c genetic deletion mice and ocular fibrosis mouse models were generated to study the role of JAM-C in vivo. EMT, proliferation, migration, and gel contraction capacities in RPE cells were examined after JAM-C knockdown by siRNAs. RNA sequencing, co-IP, ChIP-qPCR, and luciferase reporter assay were performed to investigate the underlying mechanisms. Subretinal injection of adeno-associated virus, immunofluorescence, western blot were performed to evaluate the potential of JAM-C in preventing ocular fibrosis in different mouse models.

Results

Markedly reduced JAM-C expression was found in patients with ocular fibrosis. Genetic deletion of Jam-c in mice exacerbated ocular fibrosis, and JAM-C knockdown triggered the EMT process in RPE cells. Mechanistically, we reveal that JAM-C inhibits ocular fibrosis by suppressing the nuclear localization and function of TAZ, which otherwise binds to KLF6 to promote its expression and activity to initiate the EMT cascade. Importantly, AAV-mediated JAM-C augmentation alleviated ocular fibrosis in different mouse models.

Conclusion

Our findings unveil a novel function of JAM-C in preventing ocular fibrosis by inhibiting the TAZ/KLF6 pathway, and suggest new therapeutic possibilities for the treatment of fibrotic diseases

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来源期刊

Journal of Advanced Research Multidisciplinary-Multidisciplinary

CiteScore

21.60

自引率

0.90%

发文量

280

审稿时长

12 weeks

期刊介绍： Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences. The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.