CUL4B对胰岛delta细胞的调控作用及机制

The inappropriate regulation of the islet circuit is one of the most important causes for the development of Diabetes. Among the islet circuit, the pancreatic δ cells secret somatostatin and play important roles in regulation of the homeostasis of the pancreatic β cells and islets. However, the regulatory mechanism of pancreatic δ cell itself and how pancreatic δ cell regulates homeostasis of islets is less known. Among the Cullin family members, Cul1 and Cul3 were known to play important roles in the regulation of the function of the islets. In contrast, whether another Cullin family member Cul4b participated in regulation of islet function is unknown. Recently, we have found that the conditional knockout of the Cul4b in pancreatic δ cell severely impaired glucose metabolism and homeostasis of the pancreatic islets. Based on these previous discovery, we proposed to utilize the Cul4b pancreatic δ cell conditional knock out mice, combination with multiple genetic tools, in vivo and in vitro experiments, different techniques from cell biology, electrophysiology and biochemistry, to elucidate the function and its underlying mechanism of Cul4b in regulation of islet homeostasis, in normal and different physiological or pathological conditions.

胰岛细胞环路异常是糖尿病发病的重要原因之一。在胰岛细胞环路中，胰岛δ细胞分泌生长抑素，从而对β细胞及胰岛的稳态有重要的调控作用。然而，胰岛δ细胞自身受调控及其如何调控胰岛稳态的机制确知之甚少,是目前国际上的研究热点也有重要科学意义。目前已知Cullin家族一些成员在胰岛中有重要功能，但其成员Cul4b 在胰岛中的功能却未知。我们最近的研究发现，在胰岛δ细胞中特异性敲除Cul4b会严重影响糖代谢和胰岛稳态。基于这些前期工作基础，本课题拟应用胰岛δ细胞特异性敲除Cul4b的动物模型，结合多种基因工程工具小鼠，应用体内和体外实验，细胞生物学，电生理及生物化学等多种手段，阐明Cul4b对胰岛稳态调控的作用及其分子机制，以及在各种病理生理条件下Cul4b的功能和作用机制。