The Integrated Stress Response in Human Islets During Early T1D

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ABSTRACT The pathogenesis of type 1 diabetes (T1D) encompasses a spectrum ranging from aggressive autoimmunity toward islet β cells to defects in β-cell function that arise from inflammation. A perspective that has been gaining traction in recent years posits that intracellular signaling pathways arising from the β cell response to inflammation can lead to the production of aberrant proteins that serve as neoantigens that initiate or exacerbate autoimmunity. This perspective has prompted our Team to identify and intervene in intracellular signaling pathways that affect β-cell resilience as T1D progresses from the presymptomatic to symptomatic stages. This proposal takes a multidisciplinary Team Science approach that is responsive to RFA-DK-19-024 to define and intervene in early T1D disease processes affecting human islets. The integrated stress response (ISR) is a cytoprotective process whereby environmental stress signals are transduced intracellularly to activate a host of eIF2α kinases. The phosphorylation of eIF2α halts general mRNA translation initiation in an effort to redirect energy expenditure to mitigate the prevailing stress. The translationally inhibited mRNAs and their associated proteins are sequestered into intracellular stress granules (SGs), the formations of which are thought to divert cellular signaling toward an emergency response. Our preliminary data suggest that the ISR is activated in islets during early T1D, and that the pathway linking membrane-derived lipids to the production of proinflammatory lipid intermediates may trigger the ISR and the formation of SGs. We hypothesize that the activation of the ISR and formation of SGs is an early cellular response initiating β cell stress in T1D that determines cell survival and can be monitored in pre- and early T1D individuals with minimal invasiveness. Our collaborative Team will test this hypothesis through the following aims: Aim 1: Define the mechanisms of stress granule formation and their fate upon activation of the integrated stress response in human islets. Aim 2: Determine the molecular events linking lipid metabolism, activation of the ISR, and stress granule formation in human islets. Aim 3: Identify protein, RNA, and lipid cargo in EVs as putative biomarkers of the human islet integrated stress response and T1D risk. This application leverages the expertise of 6 Multi-PIs in β-cell biology, lipid and eicosanoid biology, functional genomics, proteomics, computational modeling, and clinical islet studies. The impact of this project will be to deliver new knowledge on an unstudied stress pathway in human islets and to identify and validate biomarker panels that reflect this stress state.