# Identification and activation mechanisms of vagal and spinal nociceptors in esophageal mucosa

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $352,407

## Abstract

Project Summary
Gastroesophageal reflux disease (GERD) is a major health problem in the United States, impacting over
20% of the population. In at least a quarter of these patients, symptoms caused by GERD such as
heartburn and chest pain cannot be controlled by gastric acid suppression with proton pumps inhibitors
(PPIs). This population of patients with PPI-refractory GERD have no effective medical treatment
options. Failure to understand mechanisms of persistent symptoms in this condition is a major
knowledge gap, and limits clinical therapeutic options. One potential cause of persistent symptoms in
PPI-refractory GERD patients is weakly acidic (pH>5.0) reflux. This can cause activation of pain-
mediating nerves (C-fiber nociceptors) in esophageal mucosa, but the molecular mechanisms have not
been clearly elucidated. Furthermore it is not clear whether bile acid also directly activates esophageal
C-fibers and mediates nociceptive symptoms in GERD. Our overall hypothesis is that the refluxates in
PPI-refractory GERD (mild acid and bile acids) activate esophageal nociceptive C-fiber subtypes and
contribute to persistent symptoms in refractory GERD. Determining the identity of the afferent nerve
subtype(s) and the key receptor(s) responsible for PPI refractory symptoms are crucial for development
of specific targets for this population. Over the past decade, we have identified 3 types of C-fibers in the
esophagus which express differential receptors and neurotransmitters and have different central
projections. Intriguingly, we have developed new data which demonstrated that two factors in weakly
acidic refluxate robustly stimulate esophageal C-fibers: 1) bile acids (that are quite often found in the
refluxates on PPI therapy), and 2) acid in low proton concentrations (pH=6.0, termed here mild acid). Our
published papers and preliminary data suggest that the key receptors TGR5 and TASK1/ASIC3 are likely
involved. Based on these progresses, we will first determine in aim 1 the subtypes of nociceptive afferent
nerve terminals in esophagus mucosa which are more vulnerable to refluxates. We will then elucidate
receptors mediating C-fiber activation by mild acid in aim 2. We will address the hypothesis that mild acid
activates C-fiber subtypes via combination of inhibition of potassium two-pore domain (K2P) family
channel (TASK1) and activation of cationic channels from the ASIC family (ASIC3). In aim 3, we will
elucidate receptors mediating C-fiber activation by bile acids. We hypothesize that bile acids activate C-
fiber subtype(s), which is mediated by the bile acid receptor TGR5. We will apply the approaches of gene
expression analysis, patch clamp recordings, and recordings of nerve activity originating in the C-fiber
nerve terminals. Studies will be carried out in in animal models in which neuron-selective gene
knockdown by our validated in vivo shRNA silencing strategy. Elucidation of the mechanisms by which
bile acids and mild acid activate C-f...

## Key facts

- **NIH application ID:** 9978776
- **Project number:** 5R01DK110366-04
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Thomas Edward Taylor-Clark
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,407
- **Award type:** 5
- **Project period:** 2018-08-25 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978776

## Citation

> US National Institutes of Health, RePORTER application 9978776, Identification and activation mechanisms of vagal and spinal nociceptors in esophageal mucosa (5R01DK110366-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9978776. Licensed CC0.

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