# Insulin Signaling Activates Urothelial Defenses to Reduce Urinary Tract Infection Susceptibility

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2021 · $553,600

## Abstract

Project Summary/Abstract:
Diabetes mellitus is associated with many complications, including increased infection risk. With diabetes, one
of the most common sites of infection is the urinary tract. In people with diabetes, urinary tract infection (UTI) is
more common and has worse outcomes. The mechanisms that predispose people with diabetes to UTI are not
defined. A greater appreciation for the host defense mechanisms that protect the urinary tract from microbial
insult is needed to develop new UTI prevention and treatment strategies. This application’s objective is to identify
how insulin signaling regulates innate immune defenses in the bladder. Our published and supporting data
demonstrate that bladder urothelial defenses are regulated by insulin-mediated targets, including peroxisome
proliferator-activated receptor-γ (PPARγ), insulin receptor signaling, and histone deacetylase proteins.
Specifically, our data suggest PPARγ activation and histone deacetylase inhibition enhance insulin signaling,
strengthen the urothelial barrier, and enhance innate immunity, including the production of antimicrobial peptides
and the urothelial barrier. In contrast, silencing urothelial insulin receptor expression increases UTI susceptibility.
These data support our central hypothesis that insulin and insulin receptor signaling have key roles in activating
innate immune responses and regulating UTI host defense. Expanding upon these findings, we propose a
comprehensive analysis of insulin’s ability to regulate bladder urothelial defense mechanisms. Aim 1 will
determine the effects of progressive insulin resistance and diabetes on the bladder’s antibacterial defenses. We
will also investigate if activating PPARγ triggers insulin signaling to enhance immune defenses and reduce UTI
susceptibility. Aim 2 will interrogate the impact of insulin receptor signaling on the bladder’s immune defenses
and urothelial responses and repair to UTI. Aim 3 will define the effect of histone deacetylase proteins on insulin
signaling and the bladder’s immune defenses. Our long-term research goal is to identify why people with diabetes
have increased UTI risk and improve their care. By evaluating the role of insulin signaling in host defense, our
expected outcomes may have profound influence on human health as they may develop insulin-signaling targets
as new UTI therapeutics.

## Key facts

- **NIH application ID:** 10364241
- **Project number:** 1R01DK128088-01A1
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** John David Spencer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $553,600
- **Award type:** 1
- **Project period:** 2021-09-24 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364241

## Citation

> US National Institutes of Health, RePORTER application 10364241, Insulin Signaling Activates Urothelial Defenses to Reduce Urinary Tract Infection Susceptibility (1R01DK128088-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10364241. Licensed CC0.

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