# Cystitis-induced bladder dysfunction and pain

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2022 · $540,035

## Abstract

Project Summary/Abstract
Bladder Pain Syndrome (BPS)/Interstitial Cystitis (IC) is a chronic pelvic pain disorder with at least one urinary
symptom and the perception that the pain originates from the bladder. Stress exacerbates symptoms of
BPS/IC. Despite intense research, we lack understanding of how structural and functional changes in the
micturition reflex are linked to BPS/IC and how stress exacerbates symptoms, thus impeding effective
therapies. Addressing these challenges requires, in part: (1) a novel hypothesis involving NGF/TrkA/MAPK
signaling for downstream transient receptor potential cation channel subfamily vanilloid member 4
(TRPV4)/Ca2+ activation in the sensory components of the micturition reflex; (2) innovative and multidisciplinary
approaches; and (3) animal models that recapitulate the clinical signs/symptoms of BPS/IC including symptom
exacerbation (flares) precipitated by psychological stress. Our laboratory is unique in the complementary use
of several relevant models to reinforce our studies including (e.g., cyclophosphamide (CYP)-induced cystitis,
transgenic mice with chronic, urothelial overexpression of NGF (NGF-OE), repeated, low dose CYP (alone
insufficient to produce significant symptoms) coupled with repeated variate stress (RVS) to assess how stress
can exacerbate disease. Our overall hypothesis is that increases in urinary frequency and pelvic sensation that
accompany BPS/IC reflect increased expression, function and interactions of neurochemical mediators and the
sensory transducer, TRPV4, in the sensory components of the micturition reflex that favor a pro-excitatory
state. Building from our previous work, the maladaptive role(s) of NGF/TrkA/p75NTR signaling and downstream
activation of TRPV4/Ca2+ in the sensory components of the micturition reflex will be assessed as contributory
mechanisms to BPS/IC. Aim 1: Determine if interrupting NGF/TrkA/p75NTR signaling pathways reduces voiding
frequency and pelvic pain by: reducing (1) urothelial Ca2+ events; (2) urothelial ATP release and (3) bladder
afferent activity. Further interrupting NGF/p75NTR signaling reduces voiding frequency by: (1) reducing
urothelial cell apoptosis; (2) promoting urothelial cell recovery and (3) maintaining transepithelial resistance.
Aim 2: Determine if disruption of NGF signaling in the micturition pathway has short- and long-term
consequences on TRPV4/Ca2+ function in BPS/IC-like symptoms. The acute NGF-mediated TRPV4/Ca2+
BPS/IC-related responses include heightened urothelial Ca2+ signaling, urothelial ATP secretion and bladder
afferent nerve activity. Maladaptive, long-term NGF signaling promotes BPS/IC by increasing TRPV4 transcript
and protein expression. Using three models with BPS/IC-like symptoms and a multidisciplinary, cell-tissue-
systems experimental approach, we will determine: (1) underlying structural and functional changes
contributory to BPS/IC-like symptoms; (2) the influence of psychological stress on bladder function...

## Key facts

- **NIH application ID:** 10335802
- **Project number:** 5R01DK124580-02
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** MARGARET Ann VIZZARD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $540,035
- **Award type:** 5
- **Project period:** 2021-01-28 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10335802

## Citation

> US National Institutes of Health, RePORTER application 10335802, Cystitis-induced bladder dysfunction and pain (5R01DK124580-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10335802. Licensed CC0.

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