Kato Mitsuo, Abdollahi Maryam, Omori Keiko, Malek Vajir, Lanting Linda, Kandeel Fouad, Rawson Jeffrey, Tsark Walter, Zhang Lingxiao, Wang Mei, Tunduguru Ragadeepthi, Natarajan Rama
Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA.
Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA.
Mol Ther Nucleic Acids. 2024 Jun 15;35(3):102252. doi: 10.1016/j.omtn.2024.102252. eCollection 2024 Sep 10.
We investigated the role of the endoplasmic reticulum (ER) stress-regulated long noncoding RNA (lncRNA) lncMGC in pancreatic islets and the pathology of type 1 diabetes (T1D), as well as the potential of lncMGC-based therapeutics. , blood glucose levels (BGLs) and HbA1c were significantly lower in lncMGC-knockout (KO)-streptozotocin (STZ)-treated diabetic mice compared to wild-type STZ. Antisense oligonucleotides (GapmeR) targeting lncMGC significantly attenuated insulitis and BGLs in T1D NOD mice compared to GapmeR-negative control (NC). GapmeR-injected T1D Akita mice showed significantly lower BGLs compared to Akita-NC mice. hlncMGC-GapmeR lowered BGLs in partially humanized lncMGC (hlncMGC)-STZ mice compared to NC-injected mice. CHOP (ER stress regulating transcription factor) and lncMGC were upregulated in islets from diabetic mice but not in lncMGC-KO and GapmeR-injected diabetic mice, suggesting ER stress involvement, hlncMGC-GapmeR increased the viability of isolated islets from human donors and hlncMGC mice and protected them from cytokine-induced apoptosis. Anti-ER stress and anti-apoptotic genes were upregulated, but pro-apoptotic genes were down-regulated in lncMGC KO mice islets and GapmeR-treated human islets. Taken together, these results show that a GapmeR-targeting lncMGC is effective in ameliorating diabetes in mice and also preserves human and mouse islet viability, implicating clinical translation potential.
我们研究了内质网（ER）应激调节的长链非编码RNA（lncRNA）lncMGC在胰岛和1型糖尿病（T1D）病理中的作用，以及基于lncMGC的治疗潜力。与野生型链脲佐菌素（STZ）处理的糖尿病小鼠相比，lncMGC基因敲除（KO）-STZ处理的糖尿病小鼠的血糖水平（BGLs）和糖化血红蛋白（HbA1c）显著降低。与GapmeR阴性对照（NC）相比，靶向lncMGC的反义寡核苷酸（GapmeR）显著减轻了T1D非肥胖糖尿病（NOD）小鼠的胰岛炎和BGLs。与秋田-NC小鼠相比，注射GapmeR的T1D秋田小鼠的BGLs显著降低。与注射NC的小鼠相比，hlncMGC-GapmeR降低了部分人源化lncMGC（hlncMGC）-STZ小鼠的BGLs。CHOP（内质网应激调节转录因子）和lncMGC在糖尿病小鼠的胰岛中上调，但在lncMGC-KO和注射GapmeR的糖尿病小鼠中未上调，提示内质网应激参与其中，hlncMGC-GapmeR提高了来自人类供体和hlncMGC小鼠的分离胰岛的活力，并保护它们免受细胞因子诱导的凋亡。在lncMGC基因敲除小鼠的胰岛和GapmeR处理的人胰岛中，抗内质网应激和抗凋亡基因上调，但促凋亡基因下调。综上所述，这些结果表明，靶向lncMGC的GapmeR在改善小鼠糖尿病方面有效，还能维持人和小鼠胰岛的活力，具有临床转化潜力。
