# Neuroinflammatory Regulation of Colonic Mechanosensory Activity

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $349,313

## Abstract

PROJECT SUMMARY
 The enhanced colorectal mechanosensation in colonic hypersensitivity and gastrointestinal (GI) pain is
initiated and mediated by primary afferent neurons in dorsal root ganglia (DRG), perhaps by Piezo2-mediated
mechanotransduction in a subpopulation of colonic nociceptive afferent neurons. Macrophage colony-
stimulating factor (CSF1) and brain-derived neurotrophic factor (BDNF) are two potent mediators in the
genesis of mechanical pain, however, DRG nociceptive neurons do not express CSF1 receptor Csf1r and few
neurons have BDNF receptor TrkB. Macrophages and glial cells including satellite glial cells (SGCs) express
Csf1r and/or TrkB isoforms, therefore they are likely primary recipients of CSF1 and BDNF. In DRG,
macrophages and glial cells surround sensory neurons to form a neuronal-glial-immune cell triad. Upon
activation, macrophages and glial cells release a variety of inflammatory factors such as the pronociceptive
cytokine tumor necrosis factor alpha (TNFα) that can act on nearby sensory neurons. In our preliminary study,
macrophages and glial cells act differentially in producing TNFα in DRG of male and female mice in colonic
hypersensitivity models. TNFα and CSF1-conditioned human macrophage culture medium activate a subset of
Piezo2 expressing colonic afferent neurons. Macrophages are also activated by BDNF to produce TNFα. We
postulate that macrophages and glial cells are activated by CSF1 and BDNF in DRG to generate TNFα that
activates Piezo2 expressing colonic afferent neurons, leading to colonic mechanosensory sensitization. We will
pursue three interrelated Specific Aims. In AIM 1, we will distinguish the roles of macrophages and glial cells in
producing TNFα to generate neuroinflammation in DRG in male and female mice to regulate colonic
hypersensitivity. We will implement genetic tools for conditional ablation/inhibition of macrophages or glial cells,
and examine colorectal distension (CRD)-evoked mechanosensory activity by in vivo DRG imaging. In AIM 2,
we will determine Piezo2 in DRG nociceptive neurons in mediation of neuroinflammatory regulation of colonic
hypersensitivity. We will use our Piezo2 conditional knockout mouse line to perform direct neurochemical
measurement and study the functional roles of Piezo2 in mediation of neuroinflammation (TNFα)-regulated
colonic mechanosensory activity. In AIM 3, we will characterize the regulation of macrophages and glial cells
by CSF1 and BDNF in male and female mice in producing TNFα to regulate Piezo2 expressing colonic afferent
neurons. In many species and systems, the expression of TrkB receptors is sex-related. We will examine
whether TrkB receptors are sexually dimorphic in macrophages and glial cells to interpret the distinct roles of
macrophages and glial cells in colonic hypersensitivity in male and female mice, and suggest mechanism of
gender-related GI pain in patients. Our studies using in vivo, in vitro, genetic tools, and imaging techniques in
character...

## Key facts

- **NIH application ID:** 9947950
- **Project number:** 5R01DK118137-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Liya Qiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,313
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9947950

## Citation

> US National Institutes of Health, RePORTER application 9947950, Neuroinflammatory Regulation of Colonic Mechanosensory Activity (5R01DK118137-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9947950. Licensed CC0.

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