# Manipulating islet GPCR activity to promote beta cell proliferation and survival

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $425,000

## Abstract

Project Summary/Abstract
T2D incidence increases with age, in part due to a decreased ability of β cells to respond
to proliferative cues as they get older. Our lab identified the FoxM1 transcription factor as
a critical regulator of β-cell replication and survival. Foxm1 expression in islets declines
with age in mice and humans, but activation of FoxM1 in older mouse β cells increases β-
cell proliferation and mass. RNA-sequencing revealed that FoxM1 over-expression in β
cells decreases expression of EP3 and increases expression of EP4, two G protein-
coupled prostaglandin E2 (PGE2) receptors. In isolated islets from mouse and human, we
found that pharmacological inhibition of EP3 or activation of EP4 promotes β-cell
proliferation and survival. The current proposal makes use of in vivo mouse models,
human islet transplants and ex vivo islet cultures from humans with normoglycemia and
Type 2 diabetes to determine the downstream signaling pathways that mediate the effects
of inhibiting EP3 or activating EP4. Using phosphoprotein arrays of ex vivo treated mouse
islets, we identified PLCγ and PKA as acting downstream of EP3 inhibition or EP4
activation, respectively. In the current proposal we explore the hyopothesis that EP3
blockade (working through PLCγ) or EP4 activation (working through PKA) will ameliorate
diabetes and enhance human islet transplantation in vivo by increasing insulin secretion,
and enhancing β-cell proliferation and survival. We propose that FoxM1 directly activates
EP4 while repressing EP3 expression. These studies are designed to identify molecular
targets to enhance function, proliferation and survival of β cells with the goal of increasing
functional β cell mass.

## Key facts

- **NIH application ID:** 10022326
- **Project number:** 5R01DK120626-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Maureen A Gannon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,000
- **Award type:** 5
- **Project period:** 2019-09-25 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10022326

## Citation

> US National Institutes of Health, RePORTER application 10022326, Manipulating islet GPCR activity to promote beta cell proliferation and survival (5R01DK120626-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10022326. Licensed CC0.

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