核受体TLX通过Hes1调控胰岛β细胞去分化/再分化的机制研究

Diabetes is associated with β cell failure. Recent studies suggest that rather than apoptosis, β cell dedifferentiation into progenitor cell is the main reason for β cell failure. Such dedifferentiated cells may redifferentiate into β cells. These findings highlight the importance of β cell redifferentiate and offer hope of novel therapeutic paths to replenish β cells in diabetes. Hes1 is a key transcription factor to prevent progenitor cell differentiation in the developing pancreas. Our previous work indicates that nuclear receptor TLX which plays an essential role in neural stem cells dedifferentiation can suppress the expression of Hes1. And we also found that TLX was downregulated in β cells exposed to high glucose and knockdown of TLX in β cells resulted in decreased insulin secretion. Thus we hypothesize that TLX can induce β cell redifferentiation via inhibition of Hes1, and then improve β cell function. The current study aim to explore the effect of TLX on β cell dedifferentiation and redifferentiation, and the underlying mechanism. Finally, the project may provide a novel therapeutic strategy for diabetes.

胰岛β细胞衰竭是糖尿病发生发展的主要原因。最新观点认为糖尿病时胰岛β细胞数量减少的主要原因不是凋亡，而是去分化为祖细胞，如何使去分化细胞再分化为功能性β细胞对糖尿病的治疗具有重要意义。Hes1是阻止祖细胞向β细胞分化的关键因子。我们前期研究发现核受体TLX作为神经干细胞增殖及分化的重要调控因子，可以抑制Hes1表达，且TLX在高糖环境下的胰岛β细胞中低表达，干扰TLX表达使β细胞胰岛素分泌减少。因此我们推测：TLX可通过下调Hes1表达促进去分化β细胞再分化，恢复胰岛素分泌功能。本项目拟在体内及体外水平探讨TLX对胰岛β细胞去分化及再分化的影响及调控机制，为糖尿病的治疗提供新的策略。

胰岛β细胞去分化是导致糖尿病时β细胞数量减少的重要原因，如何使去分化细胞再分化为功能性β细胞对糖尿病的治疗具有重要意义。本项目旨在通过干预核受体TLX的表达，来明确其在 β 细胞去分化及再分化中的作用，为糖尿病的治疗提供新的靶点。项目按计划进展顺利。通过构建TLX基因敲除小鼠，发现在高糖高脂代谢应激条件下，TLX的表达下调导致β细胞去分化，胰岛素分泌水平下降，小鼠血糖水平升高，β细胞分化关键调控因子Hes1表达上调。TLX基因敲除小鼠尾静脉注射Hes1干扰慢病毒抑制Hes1表达能促进去分化β细胞再分化为功能性β细胞，恢复胰岛素分泌能力。研究结果为糖尿病的治疗提供了新的思路。