nPOD. Current nPOD Projects

Role of Monogenic Diabetes, Integrated Stress Response, mTOR and NR4A genes in Type 1 Diabetes

To date, over 60 loci have been identified, including the HLA and insulin regions and various single nucleotide polymorphisms (SNPs), conferring genetic susceptibility for type 1 diabetes (T1D); however, a number of these loci do not correspond to specific genes and as such, do not infer disease mechanisms or etiology. We have taken an innovative strategy to identify genes/biomarkers functionally and phenotypically associated with autoantibody positivity (AAB+, considered pre-T1D) and T1D, exploring early T1D pathogenic determinants in human pancreas. Our preliminary data demonstrate that genes associated with monogenic diabetes, which result from Mendelian inherited single gene mutations and are intrinsically non-redundant, display altered expression in pancreata from AAB+ and/or polygenic T1D. Using RTqPCR on total RNA from human pancreata from the Network for Pancreatic Organ donors with Diabetes (nPOD), we studied expression of 42 monogenic diabetes genes. We identified 19 genes induced in T1D versus control donor pancreata. 8 of the induced genes were functionally linked to the unfolded protein response (UPR): EIF2AK3 (PERK), head of one of three canonical UPR branches, exhibited the highest induction in T1D pancreata. Our data strongly argue that the T1D pancreas exhibits an integrated stress response (ISR), potentially in response to pathological challenges. Given that other stresses can activate the ISR, also regulating protein synthesis and cell viability, we will investigate pathways with logical overlap, namely those associated with mTOR (mammalian target of rapamycin) and NR4A (nuclear orphan receptor) and these test the hypothesis that differential gene expression in human pancreas and blood represent prognostic, diagnostic and therapeutic biomarkers/targets in T1D or pre-T1D.


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