# RESEARCH REGULATION OF MATURE BETA CELL FUNCTION BY THE TRANSCRIPTION FACTOR FOXM1

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $368,438

## Abstract

Abstract
Type 2 Diabetes (T2D) is a disease affecting more than 20 million people in the United States alone. T2D
results from the proliferative and functional failure of the insulin-producing β-cells within the Islets of
Langerhans. Successful long-term treatment of T2D may require improvement in both performance and
replication of β-cells.
FoxM1 is required for β-cell replication postnatally and in the adult pancreas. I have previously shown male-
specific restoration of aged β-cell proliferative potential and enhanced insulin secretion in mice that inducibly
express a constitutively active FoxM1. Although the mechanisms of these gender-specific effects in β-cells are
unknown, FoxM1 interacts with the estrogen receptor α (ERα) at transcriptional sites in other cell types.
Moreover, the functional targets as FoxM1 as well as its co-regulators and cooperative transcription factor
binding partners at both proliferative and functional targets are relatively unknown and completely unexplored
in the β-cells. The experiments proposed here will remedy this dearth of knowledge.
In Aim 1a, I will determine if FoxM1 and ERα are cooperative binding partners using MOW-ChIP in sorted
proliferating and quiescent β-cells from both male and female islets. I will then investigate the role of ERα
during FoxM1-mediated enhanced insulin secretion using genetic and pharmacological inhibition of estrogen
signaling. In Aim 1b, I will study whether FOXM1 is required for normal insulin secretion in EndoC-βH3 cells. I
will identify functional targets of FoxM1 using RNA-Seq on β-cells FACS-sorted from wild-type and FoxM1-
deficient islets. I will then examine the potential roles of these targets downstream of activated FoxM1 in
cultured mouse islets using pharmacological or genetic ablation.
In Aim 2, I will explore how FoxM1 distinguishes between proliferative targets, which are expressed in all
tissues, and β-cell-specific functional targets. To accomplish this Aim, I will implement de novo motif analysis
by mining the MOW-ChIP data collected in Aim 1. I will also perform immunoprecipitation against FOXM1 in
human islets to identify FOXM1 co-factors. Predicted and immunoprecipitated factors will be tested in human
islets and pancreatic sections by Re-ChIP, proximity-mediated ligation assays, and assays to identify
synergistic effects with FOXM1 on β-cell function.
The experiments proposed in this grant will test the overall hypothesis that FoxM1 upregulates genes that
promote glucose-stimulated insulin secretion and that these functional genes are controlled differently than the
cell-cycle progression genes controlled by FoxM1. These Aims collectively will help identify potential druggable
targets for future therapies in treating T2D.

## Key facts

- **NIH application ID:** 10167696
- **Project number:** 5R01DK110183-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Maria L Golson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,438
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167696

## Citation

> US National Institutes of Health, RePORTER application 10167696, RESEARCH REGULATION OF MATURE BETA CELL FUNCTION BY THE TRANSCRIPTION FACTOR FOXM1 (5R01DK110183-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10167696. Licensed CC0.

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