Molecular Genetics of Hereditary Endoplasmic Reticulum Diabetes

摘要 内质网(ER)最为人所知的作用是蛋白质折叠、钙存储和 脂类代谢。细胞器还整合了许多其他分子途径，并对细胞 钙稳态、还原-氧化调节和细胞死亡。考虑到许多重要而复杂的功能 对于ER来说，它的失败会引发一系列疾病也就不足为奇了。已有研究表明，监管失调 内质网稳态失调可能是1型和2型糖尿病患者β细胞功能障碍和死亡的基础。 单基因形式的糖尿病，包括Wolfram综合征、Wolcott-Rallison综合征、小头症、癫痫、 和糖尿病综合征(MEDS)，以及由致病变异引起的胰岛素基因突变引起的糖尿病 分别为WFS1和CISD2、EIF2AK3、IER3IP1和INS基因。为了进一步了解这一贡献 内质网功能障碍与β细胞死亡的关系以及设计针对糖尿病的内质网新疗法，我们需要建立 影响内质网稳态的基因变异的功能研究，设计针对共同分子的治疗方法 在内质网应激的β细胞中改变通路，并确定参与β细胞功能障碍和死亡的其他ER基因。在……里面 在这项提议中，我们将使用泛函来表征WFS1和CISD2、EIF2AK3、IER3IP1和INS变体 针对β细胞中改变的常见分子通路的分析和生物信息学以及测试新的治疗方法 表达WFS1和CISD2、EIF2AK3、IER3IP1和INS基因的致病变异体。成功完成 这项研究的结果将为遗传性ER糖尿病的精确医学的建立奠定基础。

Abstract The endoplasmic reticulum (ER) is best known for its role as the locus of protein folding, calcium storage, and lipid metabolism. The organelle also integrates numerous other molecular pathways and contributes to cellular calcium homeostasis, reduction-oxidation regulation, and cell death. Given the many vital and complex functions of the ER, it is little wonder that its failure can trigger a range of diseases. It has been shown that dysregulation of ER homeostasis may underlie β cell dysfunction and death in type 1 and type 2 diabetes, as well as in monogenic forms of diabetes, including Wolfram syndrome, Wolcott-Rallison syndrome, microcephaly, epilepsy, and diabetes syndrome (MEDS), and mutant insulin gene-induced diabetes caused by pathogenic variants in the WFS1 and CISD2, EIF2AK3, IER3IP1, and INS genes respectively. To further understand the contribution of ER dysfunction to β cell death and design novel treatments targeting ER for diabetes, we need to establish functional studies of gene variants affecting ER homeostasis, design treatments targeting common molecular pathways altered in ER stressed β cells, and identify other ER genes involved in β cell dysfunction and death. In this proposal, we will characterize WFS1 and CISD2, EIF2AK3, IER3IP1, and INS variants using functional assays and bioinformatics and test novel treatments targeting the common molecular pathways altered in β cells expressing pathogenic variants of WFS1 and CISD2, EIF2AK3, IER3IP1, and INS genes. Successful completion of this study will lead to the establishment of precision medicine for hereditary ER diabetes.