Type 1 diabetes mellitus (T1D) results from immune-mediated destruction of pancreatic β-cells leading to loss of insulin production, unsuppressed glucose production, and hyperglycemia. Despite intensive research on T1D pathogenesis, the mechanisms by which initial signals trigger autoimmunity, the identity of intracellular mediators that lead to β-cell demise and how β-cells communicate with immune cells remain poorly understood.
The ER orchestrates protein synthesis, folding and trafficking in the cell and disruption of the ER's adaptive capacity results in activation of the UPR. Under chronic stress conditions, these UPR mediators engage many different inflammatory and stress signaling pathways that are critical for disease pathologies including insulin resistance, obesity, type2 diabetes and atherosclerosis. Although little is known about the role of ER stress and defective UPR in T1D pathogenesis emerging data suggest involvement of an abnormal UPR in β-cell pathophysiology and diabetes. However, the specific regulation, function and the significance of the distinct arms of UPR in β-cells and how β-cell ER stress can affect the function, regulation and differentiation of immune cells in the pathogenesis of T1D remain insufficiently understood.
The research in our laboratory currently focuses on detailed characterization of β-cell UPR in type 1 diabetes mouse models and investigation of the β-cell-immune system cross talk in the presence of β-cell specific defects of UPR. We believe results from these studies will generate the basis for further mechanistic studies and will potentially translate into the development of novel and effective therapeutic strategies.