内质网相关降解障碍诱导的胰岛Beta细胞功能衰竭机制与干预措施研究

胰岛素抗性状态下胰岛Beta细胞功能失败是2型糖尿病的根本原因，但其发生机理不清、临床干预手段有限。解决这个问题具有重要理论和临床意义。内质网相关降解（ERAD）是细胞内一种蛋白质质量检控机制。我们的前期研究发现ERAD障碍导致小鼠胰岛素合成分泌受阻、去分化因子表达增高。离体细胞实验证明，上调ERAD功能或补充微量元素镁离子增强Beta细胞活性、改善胰岛素分泌。为进一步阐明ERAD障碍是否参与诱导胰岛Beta细胞功能失败并验证ERAD作为药物干预靶点的可能性，本项目拟开展下列研究：（1）使用遗传示踪方法检测ERAD缺失是否导致Beta细胞去分化（2）通过转基因小鼠实验验证上调ERAD功能是否帮助胰岛Beta细胞抗内质网应激；（3）通过膳食补充验证微量元素镁离子是否可以增强胰岛Beta细胞功能和活性。本项目旨在揭示2型糖尿病的致病机制，并为其预防和治疗提供新的药物靶点。

Functional failure of pancreatic beta cells in the context of insulin resistance leads to type 2 diabetes (T2D), but the underlying pathological mechanisms remain elusive. Endoplasmic reticulum-associated degradation (ERAD) is a cellular protein quality control mechanism. Our preliminary results show that ERAD deficiency causes blunted insulin secretion and increased expression dedifferentiation biomarkers in mouse islets. Enhancing ERAD function or treatment with trace element Mg2+ increases the viability and protein secretion of cultured beta cell line. To further assess whether ERAD deficiency is causally involved in the pathogenesis of, and to test the possibility of ERAD as a drug target for prevention and treatment of T2D, we propose the following studies: (1) To determine through genetic lineage tracing whether ERAD deficiency causes beta cell dedifferentiation; (2) To test in transgenic mice if enhancing ERAD function protects beta cell from endoplasmic reticulum stress and reduces the risk of developing T2D; (3) To test whether supplementation of Mg2+ improves beta cell function and viability. The novel findings from the proposed research are expected to help better understand the molecular pathogenesis of, and consequently, to develop more effective therapies for the prevention and treatment of T2D.