# Transcriptional and Translational Mechanisms Governing Beta Cell Function

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $555,232

## Abstract

ABSTRACT
 The concepts underlying the pathogenesis of type 1 diabetes (T1D) have seen a renaissance in recent
years. Recently, there has been increased appreciation that β cells are an active, rather than passive, player
in the disease process. A key recognition is that environmental insults in T1D (e.g. inflammation, virus) trigger
molecular responses in β cells that potentiate detrimental communication with immune cells. In the next cycle
of this R01 award, we propose to extend our work to link these cell-autonomous signaling pathways to their
role in T1D pathogenesis. Our published and preliminary data demonstrate that a key inflammatory signaling
pathway in β cells, the 12-lipoxygenase (12-LOX)/Gpr31 pathway, potentiates the integrated stress response
(ISR). The integrated stress response (ISR) is a cytoprotective process whereby environmental stress signals
such as proinflammatory cytokines, viral infections, and nutrient deprivation 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 allay the prevailing stress. The blockade of this pathway though genetic
or pharmacologic means suppresses the ISR, reduces β cell-immune cell crosstalk, and substantially
diminishes T1D development in NOD mice. We hypothesize that inflammatory stress signaling within β cells
exacerbates the ISR to both initiate and propagate autoimmunity in T1D. We propose the following 3 aims:
Aim 1: Elucidate how 12-LOX/Gpr31 signaling links inflammatory signals to the ISR to drive T1D outcome.
Aim 2: Determine how the β cell integrated stress response (ISR) promotes T1D susceptibility.
Aim 3: Determine the mechanisms by which the 12-LOX/Gpr31 pathway and the ISR enhance cellular
crosstalk between β cells and immune cells to promote autoimmunity in T1D.
 Whereas T1D is an autoimmune disease, therapies that have exclusively targeted the immune system
have seen variable success. Recent clinical successes using drugs that block inflammation and stress
pathways more broadly suggest a need to revise therapeutic approaches to T1D. Collectively, the work
proposed in this application will harness the momentum behind β cell research in T1D to interrogate how
stress signaling pathways influence crosstalk with the immune system to potentiate autoimmunity. We are
competitively positioned with the relevant collaborative expertise and state-of-the-art, manipulable model
systems across the translational spectrum from lower organisms to humans to test our underlying hypothesis
and validate novel targets for T1D disease modification.

## Key facts

- **NIH application ID:** 10823347
- **Project number:** 5R01DK060581-21
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Raghavendra G Mirmira
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $555,232
- **Award type:** 5
- **Project period:** 2002-03-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823347

## Citation

> US National Institutes of Health, RePORTER application 10823347, Transcriptional and Translational Mechanisms Governing Beta Cell Function (5R01DK060581-21). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10823347. Licensed CC0.

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