保留的DNA损伤检查点途径可预防长期1型糖尿病的并发症。
Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes.
作者信息
Bhatt Shweta, Gupta Manoj K, Khamaisi Mogher, Martinez Rachael, Gritsenko Marina A, Wagner Bridget K, Guye Patrick, Busskamp Volker, Shirakawa Jun, Wu Gongxiong, Liew Chong Wee, Clauss Therese R, Valdez Ivan, El Ouaamari Abdelfattah, Dirice Ercument, Takatani Tomozumi, Keenan Hillary A, Smith Richard D, Church George, Weiss Ron, Wagers Amy J, Qian Wei-Jun, King George L, Kulkarni Rohit N
机构信息
Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
出版信息
Cell Metab. 2015 Aug 4;22(2):239-52. doi: 10.1016/j.cmet.2015.07.015.
The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration ≥ 50 years) with severe (Medalist +C) or absent to mild complications (Medalist -C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist -C. In silico analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced susceptibility to genotoxic stress that worsened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. We propose miR200-regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes.
1型糖尿病（T1D）并发症发生的潜在机制目前仍知之甚少。对患有长期T1D（病程≥50年）且伴有严重并发症（金牌+C组）或无至轻度并发症（金牌-C组）患者的诱导多能干细胞（iPSC）进行疾病建模，结果显示金牌+C组细胞的生长、重编程和分化受损。基因组学和蛋白质组学分析表明，DNA损伤检查点蛋白的差异调节有利于金牌-C组细胞免受细胞凋亡。计算机模拟分析显示，金牌组之间DNA损伤检查点因子的表达模式改变是miR200的作用靶点，miR200在金牌+C组血清中的表达显著升高。值得注意的是，从金牌+C组iPSC分化而来的神经元对基因毒性应激的敏感性增强，在miR200过表达时情况恶化。此外，在金牌+C组成纤维细胞和iPSC中敲低miR200可挽救检查点蛋白表达并减少DNA损伤。我们提出，miR200调节的DNA损伤检查点途径可能是治疗糖尿病并发症的潜在治疗靶点。
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