# The 12-HETE receptor Gpr31 in the -cell pathogenesis of type 1 diabetes

> **NIH NIH R03** · UNIVERSITY OF CHICAGO · 2020 · $162,000

## Abstract

Abstract
This application is responsive to RFA-RM-19-011 and will focus on a poorly characterized GPCR in the
Illuminating the Druggable Genome (IDG) database known as GPR31 in the context of diabetes. Over the
past decade, our laboratory has focused on inflammation and the cellular response to inflammation as a
central mechanism that contributes to β-cell dysfunction and death type 1 diabetes (T1D) and type 2 diabetes
(T2D). Specifically, our laboratory has demonstrated that 12-lipoxygenase (12-LOX), an enzyme involved in
arachidonic acid metabolism and expressed in β-cells, is activated in the context of β-cell inflammation and
produces the eicosanoid 12-S-hydroxyeicosatetraenoic acid (12(S)-HETE). 12(S)-HETE generates
endoplasmic reticulum (ER) and oxidative stress in β cells, but the mechanism through which this occurs has
remained elusive. Deletion of the gene encoding 12-LOX in mice (Alox15), either conditionally in islets or
globally, leads to protection from spontaneous type 1-like diabetes in NOD mice and obesity-induced type 2-
like diabetes in high fat-fed mice. GPR31 has recently been de-orphaned and identified as the 12(S)-HETE
receptor. We have generated congenic Gpr31b-/- mice on the C57BL6/J background through traditional ES
cell cloning. Preliminary data suggest that Gpr31-/- mice are viable and metabolically normal, similar to Alox15-
/- mice, however it remains to be determined if GPR31 mediates the effects of 12-LOX under diabetogenic
conditions in β-cells. In this proposal, we will generate preliminary data supporting the potential role of GPR31
as a key mediator of inflammation-induced β-cell dysfunction and death, and the data and resources generated
from this proposal will be made available to the Resource Dissemination and Outreach Center (RDOC) of the
IDG program. This grant proposal continues a longstanding and productive collaboration between Drs. S.
Tersey and R. Mirmira, who are co-located at the University of Chicago. The combined expertise of Dr.
Mirmira in β cell signaling cascades and Dr. Tersey in animal models of diabetes are synergistic towards the
completion of this pilot proposal. Our Team will test the hypothesis that GPR31 promotes β-cell inflammatory
signaling and contributes to β-cell dysfunction and death in the setting of diabetes. To test this hypothesis, the
following two aims will be achieved within the timeframe allotted to this RFA:
Aim 1: Elucidate the role of GPR31 in mediating the effects of diabetogenic inflammation and 12(S)-HETE in
islets.
Aim 2: Characterize the metabolic effects of GPR31 in vivo under normal and pro-inflammatory conditions.
The primary impact of this proposal is the determination of whether GPR31 is a suitable target for drug
development in the context of diabetic inflammation.

## Key facts

- **NIH application ID:** 10047529
- **Project number:** 1R03TR003381-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Raghavendra G Mirmira
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,000
- **Award type:** 1
- **Project period:** 2020-08-19 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047529

## Citation

> US National Institutes of Health, RePORTER application 10047529, The 12-HETE receptor Gpr31 in the -cell pathogenesis of type 1 diabetes (1R03TR003381-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10047529. Licensed CC0.

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