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.

Project Narrative Endoplasmic reticulum (ER) participates in so many cellular tasks that trouble can ensue when it stops working properly, including β cell death in type 1 and type 2 diabetes. Despite the underlying importance of ER dysfunction, there is no effective diabetes treatment targeting the ER due to the complex etiologies of type 1 and type 2 diabetes. Our strategy for overcoming this challenge is to focus on monogenic forms of diabetes in which mutations in single genes are involved in ER dysfunction and disease manifestations. We will carry out molecular genetic studies of five types of ER diabetes to characterize variants using functional assays and bioinformatics and then develop novel treatments targeting the common molecular pathways altered in hereditary ER diabetes.