Molecular Genetics of Hereditary Endoplasmic Reticulum Diabetes

摘要 内质网（ER）最为人所知的作用是作为蛋白质折叠、钙储存和钙转运的场所。 脂质代谢细胞器还整合了许多其他分子途径，并有助于细胞 钙稳态、还原-氧化调节和细胞死亡。鉴于许多重要而复杂的功能 因此，它的失败会引发一系列疾病也就不足为奇了。研究表明， 雌激素受体稳态的改变可能是1型和2型糖尿病患者β细胞功能障碍和死亡的基础， 单基因型糖尿病，包括Wolfram综合征，Wolcott-Rallison综合征，小头畸形，癫痫， 和糖尿病综合征（MEDS），以及突变型胰岛素基因引起的糖尿病致病性变异， WFS 1和CISD 2、EIF 2AK 3、IER 3 IP 1和INS基因。为了进一步了解 ER功能障碍对β细胞死亡的影响，并设计针对糖尿病ER的新治疗方法，我们需要建立 影响ER稳态的基因变异的功能研究，设计针对常见分子的治疗方法， 研究了ER应激β细胞中改变的ER通路，并鉴定了参与β细胞功能障碍和死亡的其他ER基因。在 在这个建议中，我们将使用功能性的方法来表征WFS 1和CISD 2、EIF 2AK 3、IER 3 IP 1和INS变体。 测试针对β细胞中改变的常见分子途径的新型治疗方法 表达WFS 1和CISD 2、EIF 2AK 3、IER 3 IP 1和INS基因的致病变体。成功完成 这项研究的成功将导致遗传性ER糖尿病的精确医学的建立。

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.