Sel1L在胰岛β细胞生长发育调控中的作用及其机制研究

胰岛β细胞功能紊乱和失败是导致II型糖尿病的根本原因，但其致病的分子机理尚未完全清楚。近年来，本研究组采用常规基因敲除小鼠模型对一细胞质因子Sel1L在β细胞生成、功能和活性中的调控功能和机理进行了一系列的研究, 发现Sel1L具有调控胰岛干细胞分化、β细胞分裂增殖以及成熟β细胞活性的多重作用。然而由于Sel1L全身缺失导致小鼠胚胎早期死亡，无法继续探索Sel1L在成年个体的β细胞中的功能及其调控机理。本项目拟用β细胞组织条件性基因敲除小鼠模型，从β细胞生长、发育、功能和活性四方面对Sel1L在胰岛中的调控功能和机理进行系统探讨。所得研究成果将为阐明II型糖尿病发病的分子和细胞机制提供重要理论依据，并为开发抗糖尿病新药探索新的途经。

Dysfunction and failure of insulin-secreting pancreatic βcells has been shown to be responsible for the pathogenesis of type 2 diabetes (T2D). The underlying molecular mechanisms, however, are incompletely understood. Through gene-targeting in mice, we have previously shown that Sel1L, an endoplasmic reticulum (ER) protein, is required for βcell formation during mouse embryonic development. Because global disruption of Sel1L in mice causes early embryonic lethality, the physiological role of Sel1L in adult βcells and the regulatory molecular mechanisms remain unknown. In this application, we propose to use a conditional gene-targeting strategy to investigate the role of Sel1L in the regulation of postnatal βcell growth, functional and viability. The novel insight from the proposed research is expected to significantly advance our understanding of the molecular underlying βcell dysfunction and failure in T2D. Consequently, the new knowledge is highly expected to lead to novel and more effective therapeutic strategies for the prevention and treatment of T2D and other metabolic diseases.