# The Integrated Stress Response in Human Islets During Early T1D

> **NIH NIH U01** · UNIVERSITY OF CHICAGO · 2022 · $762,343

## Abstract

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.

## Key facts

- **NIH application ID:** 10440523
- **Project number:** 5U01DK127786-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Decio laks Eizirik
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $762,343
- **Award type:** 5
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440523

## Citation

> US National Institutes of Health, RePORTER application 10440523, The Integrated Stress Response in Human Islets During Early T1D (5U01DK127786-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10440523. Licensed CC0.

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