# Inhibition of TLR4 for Treatment of Cystitis Pain

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $343,125

## Abstract

PROJECT SUMMARY
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the
urinary bladder characterized by the hallmark symptoms of pelvic pain in the absence of other identified
etiologies for the symptom. IC/BPS patients also frequently have voiding dysfunction such as increased urinary
frequency and urgency. This urologic condition is significant and severely affects quality of life. Its financial
burden on the U.S. healthcare system is tremendous. Since the etiology of IC/BPS remains elusive, current
treatments are largely empirical, often dissatisfactory, and vary in efficacy. Therefore, effort to develop new
therapies for IC/BPS is greatly needed. Prior studies have suggested that altered Toll-like receptor (TLR) 4
activation may contribute significantly to the initiation and maintenance of heightened pain states in chronic
pain conditions. TLR4 is expressed in numerous cell types including neuronal and non-neuronal cells in the
central nervous system as well as immune (e.g. monocytes/macrophages) and other somatic cells (e.g.
bladder epithelial cells) in the periphery. Once activated, TLR4 mediates proinflammatory cytokine production,
leading to enhanced central and peripheral immune signaling and subsequent exaggerated nociceptive
transmission. While the effect of TLR4 inhibition on chronic pain relief has been demonstrated in multiple
animal models (e.g. inflammatory and neuropathic pain), this has not been explored in cystitis pain seen in
IC/BPS patients. Recently, we identified a major role of altered TLR4/TLR2 activations in IC/BPS. Particularly,
we observed that increased production of TLR4-mediated proinflammatory cytokines by peripheral blood
mononuclear cells is significantly associated with greater pain severity and the extent of comorbid pain in
IC/BPS patients. Consistent with our clinical findings, we found that cystitis pain is associated with elevated
systemic and central TLR4/TLR2 inflammatory responses in our validated preclinical transgenic IC/BPS-like
animal model (URO-OVA). We hypothesize that altered TLR4/TLR2 activations are responsible for IC/BPS
pain and blocking TLR4 and/or TLR2 activation can reverse cystitis pain in IC/BPS patients. To test our
hypothesis, we will use the URO-OVA model to conduct three novel and integrative Specific Aims: 1) Identify
the states of peripheral and central TLR4/TLR2 activations in cystitis pain in the URO-OVA model; 2) Quantify
systemic TLR4 inhibition versus chronic cystitis pain relief to determine the optimum level of systemic TLR4
inhibition for maximum pain relief in the URO-OVA model; 3) Develop TLR4 inhibition combination therapies
for cystitis pain in the URO-OVA model. We anticipate that our study will provide new insights for the
mechanisms of cystitis pain and a basic research platform for future development of clinical strategies for
treatment of IC/BPS pain. Knowledge gained from this study will be useful for ultim...

## Key facts

- **NIH application ID:** 9957050
- **Project number:** 5R01DK111396-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** YI LUO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,125
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957050

## Citation

> US National Institutes of Health, RePORTER application 9957050, Inhibition of TLR4 for Treatment of Cystitis Pain (5R01DK111396-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9957050. Licensed CC0.

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