# Chromogranin A as a Regulator of Urothelial Antimicrobial Responses During Urinary Tract Infection

> **NIH NIH R21** · LOYOLA UNIVERSITY CHICAGO · 2020 · $190,625

## Abstract

#7. PROJECT SUMMARY
A major gap exists in our understanding of how neuroendocrine mediators impact urothelial innate immune
regulation to increase the risk for urinary tract infection (UTI) in females. During UTI, epithelial Toll-like
Receptors (TLRs) detect microbial components to induce antimicrobial peptides (AMPs), innate immune
factors that exhibit direct microbicidal activity and stimulate subsequent immune responses. We previously
determined that psychological stress and the loss of the neuroendocrine protein, chromogranin A (CHGA),
increased the susceptibility to skin infection by decreasing AMP responses. Our objective is to expand this
area of urinary clinical research by identifying a role for psychological stress and CHGA in modulating
urothelial AMP responses. Our long-term goal is to identify the mechanisms by which CHGA modulates TLR-
dependent urothelial AMP responses, and relate these changes to UTI risk in humans. The objective here is to
characterize CHGA-mediated AMP dysfunction in human urothelial cells and in a mouse model of Escherichia
coli (UPEC) infection. Our hypothesis is that aberrant production of CHGA/Cst contributes to UPEC
susceptibility by compromising inherent urothelial AMP responses. Our hypothesis was formulated based on
observations from our lab that the loss of CHGA increases the susceptibility to skin bacterial infection in mice,
and that catestatin, a CHGA-derived peptide released in response to stress, modulates epithelial AMP
responses. Our rationale is that no one has investigated the role of CHGA in TLR-dependent urothelial AMP
responses in the context of UTI, even though activation of the neuroendocrine system is impaired in several
disorders of the female urinary tract. Driven by compelling published data in skin and pilot data in urothelial
cells, our hypothesis will be evaluated by addressing two Specific Aims: 1.) We will use pharmacologic
approaches to assess the effect of CHGA and catestatin peptides (wild-type and mutant) on AMP production
and activity in primary human urothelial cells (HUCs) and urothelial organotypic rafts 2.) We will determine the
role of CHGA in the urothelial AMP response to UPEC infection in vivo using mice deficient in urothelial CHGA.
Our approach is innovative by using high-throughput molecular and proteomic approaches and tissue-specific
knock-out mice to establish a role for CHGA in modulating urothelial AMP responses during UPEC infection.
The proposed research is significant, because it will begin to dissect the mechanisms of urothelial AMP
dysregulation caused by CHGA deficiency, in a controlled setting, using novel human urothelial cell and
genetic mouse models in parallel, which will provide the foundation for future R01 applications and human
clinical trial networks focused on UTIs. Our study results are anticipated to greatly improve our knowledge of
urothelial AMP regulation by CHGA, which may lead to novel strategies to manipulate CHGA-mediated AMP
response...

## Key facts

- **NIH application ID:** 9858249
- **Project number:** 5R21AI142528-02
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** Katherine Amanda Radek
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $190,625
- **Award type:** 5
- **Project period:** 2019-02-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858249

## Citation

> US National Institutes of Health, RePORTER application 9858249, Chromogranin A as a Regulator of Urothelial Antimicrobial Responses During Urinary Tract Infection (5R21AI142528-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858249. Licensed CC0.

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