Recent evidence has implicated pathways intrinsic to the β cell, such as endoplasmic reticulum (ER) stress, as potential triggers of T1D. ER stress is increased by the loss of ER Ca2+, leading to decreased β cell function and increased β cell apoptosis. Maintenance of intraluminal ER Ca2+ stores is primarily regulated by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2) pump, and we have shown that β cell SERCA2 expression is reduced in islets from mouse models of T1D prior to, and after, disease onset. Thus, we hypothesized that SERCA2-mediated ER Ca2+ dyshomeostasis could be a major contributor to T1D development. To test this, we generated a mouse model haploinsufficient for SERCA2 on the NOD background (NOD-S2+/-). Compared to wild type littermates (NOD-WT), NOD-S2+/- mice had a higher incidence of diabetes (p<0.0001) and incidence was accelerated (14.5 wks vs. 19 wks, p<0.0001). Prior to diabetes onset, NOD-S2+/- islets also had increased MHC-I expression, which has been reported to follow increased ER stress and lead to increased β cell immunogenicity. To test whether SERCA2 activation may have beneficial therapeutic effects, we treated NOD-WT and NOD-S2+/- mice with CDN1163, an allosteric activator of SERCA2, from 6-8 wks of age and observed a two week delay in NOD-S2+/- average onset (p<0.05). To characterize patterns of islet immune infiltration in response to SERCA2 loss, we are utilizing the CODEX multiplexed tissue imaging platform. Our pilot study used a ten antibody panel to label and image spleen, pancreatic lymph nodes, and islets from NOD-WT. Using Indiana University-developed software, Volumetric Tissue Exploration Analysis, our preliminary analysis yields a high fidelity of nuclear segmentation and low (∼10%) false positive identification of markers. Taken together, our data suggest that loss of SERCA2 exacerbates T1D development and indicates SERCA2 may be a novel T1D therapeutic target.
R.N. Bone: None. C.A. Reissaus: None. T. Kono: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb.