# Molecular and cellular mechanisms of visceral pain and cross-organ sensitization

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $730,883

## Abstract

PROJECT SUMMARY/ABSTRACT
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disorder characterized clinically by recurring
episodes of pelvic pain and increased urination frequency, significantly impairing patients' quality of life. Irritable
bowel syndrome (IBS) is a multifactorial disorder characterized by abdominal pain and altered bowel habits, as
well as other somatic, visceral, and psychiatric comorbidities. Despite distinct origins, recent studies have shown
a strong overlap between both syndromes and this pathological co-occurrence is believed to be responsible for
the comorbidity of a number of lower urinary tract and colonic disorders, including, but not limited to, IBS,
inflammatory bowel disease (IBD), overactive bladder (OAB), and IC/BPS. There is an unmet medical need in
terms of effective diagnostics and treatment. One of the challenges is a lack of understanding of the molecular
and cellular mechanisms underlying the pathogenesis of neurogenic bladder pain. Moreover, how bladder
inflammation promotes colon sensitization is poorly understood.
Pilot studies showed that MrgprB2 is required for bladder pain and sensitization of colon to mechanical
stimulation induced by intravesical instillation of LL-37. These observations led us to frame the hypothesis that
MrgprB2+ mast cell (MC)-TRPV1+ nociceptor clusters mediate bladder pain and inter-organ sensitization
between the bladder and colon. In this grant proposal we will: 1) Use chemogenetic inhibition of mast cells and
virally mediated ablation of TRPV1+ bladder-innervating nociceptors to investigate in vivo functions of the
MrgprB2+ MC-TRPV1+ nociceptor clusters in MrgprB2-dependent bladder pain; use humanized mouse model
with targeted expression of MrgprX2 in MCs to test if human MrgprX2 also impacts bladder pain; use TRPV1+
nociceptor specific Piezo2 cKO mice and virally mediated ablation of Piezo2 function in bladder-innervating
nociceptors to determine if nociceptor-expressed mechanosensitive Piezo2 channels mediate bladder pain
induced by various irritants including LL-37, compound 48/80, or CYP. 2) Focus on differentiating visceral
nociceptors innervating both the bladder and colon and use unique chemical- and viral-mediated approaches to
either ablate or chemogenetically inhibit these distinct nociceptors to determine if they are required for the
generation of colon pain induced by bladder inflammation caused by LL-37, compound 48/80, or CYP; test if
MC-derived LTC4-neuronal CysLTR2 axis contributes to bladder pain and mediates inter-organ cross
sensitization in the colon.
Our findings will provide cellular and molecular basis for bladder pain and bladder-colon cross sensitization
mediated by the MrgprB2+ mast cell-TRPV1+ nociceptor clusters and will undoubtedly lead to new therapeutic
approaches for treating visceral pain.

## Key facts

- **NIH application ID:** 10997075
- **Project number:** 1R01DK141106-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Hongzhen Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $730,883
- **Award type:** 1
- **Project period:** 2024-08-20 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997075

## Citation

> US National Institutes of Health, RePORTER application 10997075, Molecular and cellular mechanisms of visceral pain and cross-organ sensitization (1R01DK141106-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997075. Licensed CC0.

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