PARP-1调控MAPK通路参与年龄相关胰岛β细胞再生的机制研究

β cell regeneration is the hope for diabetes therapy，but the mechanism is not yet clear. Our previous study found that homeostasis of glucose metabolism was significantly better in aging PARP-1-/ - mice than aging wild-type mice with MAPK signaling pathway activation, but the mechanism should be further explored. We propose the hypothesis: PARP-1/MAPK signalling controls age-dependent proliferation in pancreatic β-cells. In this study, we will use islets, PARP-1 knockout mice and p16INK4a knockout mouse as study models, to explore the effect of PARP-1 on age-dependent proliferation in pancreatic β-cells and explore the mechanisms involved. The outcome will not only shed light on the mechanism of age-dependent proliferation in pancreatic β-cells, but also provide novel perspectives to therapy of diabetes.

胰岛β细胞再生是糖尿病根治的希望，但其调控机制尚未明确。我们前期研究发现老龄PARP-1–/–小鼠的葡萄糖代谢稳态明显优于同龄野生小鼠，β细胞再生数量显著增多，同时，MAPK信号通路激活，但其机制有待进一步探讨。为此，我们提出假说：PARP-1通过MAPK信号通路调控p16INK4a的表达，参与年龄相关β细胞再生能力的改变。为验证这一假说，我们将通过体外分离培养的胰岛、PARP-1基因敲除小鼠及p16INK4a基因敲除小鼠模型，采用RT-PCR、Western blot、慢病毒载体转染等手段，从分子、细胞、组织及动物水平多层次探讨PARP-1对年龄相关胰岛β细胞再生能力的重要作用及机制。本研究将从PARP-1这个新视点为提示年龄相关胰岛β细胞再生的机制奠定基础，为延缓老年糖尿病的发生发展及糖尿病的细胞治疗提供新的思路和科学依据。