在小岛中恢复了UBE2C表达,通过ubiquitinatingPER1在小鼠中促进β细胞再生
Hemin Jiang1, Shuai Zheng1, Yu Qian1
1Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Cellular and molecular life sciences : CMLS
|July 24, 2023
概括
无素结合酶2C (UBE2C) 通过降解PER1促进小岛β细胞的再生,为2型糖尿病和胰岛素缺乏症提供潜在的治疗方法.
科学领域:
- 内分泌学 在内分泌学.
- 分子生物学分子生物学
- 糖尿病研究 糖尿病研究
背景情况:
- 胰岛素缺乏,糖尿病的标志,与受损的岛屿β细胞增殖有关.
- NKX6.1是β细胞增殖的关键转录因子,UBE2C被确定为下游目标.
- 在β细胞功能和再生中UBE2C的确切作用需要进一步研究.
研究的目的:
- 阐明UBE2C在小岛β细胞增殖和再生中的功能和机制.
- 研究UBE2C在治疗糖尿病相关β细胞功能障碍中的治疗潜力.
主要方法:
- 从小鼠的岛屿β细胞中UBE2C表达的分析.
- 产生和研究β细胞特异性UBE2C淘汰小鼠 (βUbe2cKO).
- 研究UBE2C与CUL1的相互作用以及通过ubiquitin-proteasome通路调节PER1降解.
- 在体内和体外实验评估UBE2C操纵对β细胞增殖和葡萄糖代谢的影响.
- 在STZ诱导的糖尿病小鼠模型中UBE2C的lentiviral转导.
主要成果:
- 活跃增殖的小岛贝塔细胞的一个亚群高度表达UBE2C.
- 在断奶和HFD养的小鼠中,UBE2C通过细胞循环更新途径诱导β细胞的补偿增殖.
- 在βUbe2cKO小鼠中,UBE2C的丧失导致ββ细胞增殖的减少,胰岛素缺乏,以及2型糖尿病.
- UBE2C通过无素-蛋白酶体系统促进PER1降解,而PER1抑制可以挽救UBE2C淘汰诱导的β细胞生长缺陷.
- 在小岛中UBE2C的过度表达部分缓解了糖尿病小鼠的高血糖和葡萄糖不耐受.
结论:
- UBE2C通过促进昼夜时钟抑制器PER1.1的泛化和降解来积极调节β细胞的增殖.
- UBE2C在维护β细胞质量和功能方面发挥着关键作用,对于预防胰岛素缺乏和糖尿病至关重要.
- UBE2C是促进小岛贝塔细胞再生和治疗糖尿病的有希望的治疗标.
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