# Uterine bitter taste receptors in pregnancy and preterm labor management

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $340,611

## Abstract

Abstract
Uterine contractility is regulated and controlled by a complex system such that pregnancy is maintained and
parturition occurs at full term. Coordinated uterine contractions occurring prior to 37 weeks gestation, i.e.,
preterm labor (PTL), could lead to preterm birth (PTB) which affects 15 million newborns and causes 1 million
neonatal deaths worldwide annually. Given that contractions are a central feature of PTL, tocolytics are used
in PTB management, yet current tocolytics are not sufficiently effective. We recently found that uterine smooth
muscle (USM) cells from mouse and human express bitter taste receptors (TAS2Rs) and their canonical
signaling components (i.e., G-protein gustducin and PLCβ2). Also bitter tastants (e.g., phenanthroline (PHEN),
and chloroquine, a FDA-approved antimalarial drug) relax uterine strips pre-contracted by uterotonics (e.g.,
oxytocin and prostaglandin F2α) more completely than current commonly used tocolytics (i.e., nifedipine,
indomethacin and MgSO4). Moreover, bitter tastants (e.g., chloroquine) can prevent mouse PTB induced by
bacterial endotoxin lipopolysaccharide (LPS) and nuclear progesterone receptor antagonist RU486 more often
than commonly used tocolytics and in a gustducin dependent manner. In our preliminary studies, we further
found that (1) PHEN can stop pregnant mouse uterine contractions induced by serotonin, endothelin-1,
neuromedin S and U-46619, all pathophysiological mediators in the uterus, (2) Tas2r expression in USM is
decreased when pregnant mice approach parturition and is restored after labor, and (3) the simultaneous
deletion of the three main Tas2rs expressed in USM increases the probability of PTB in mice. We therefore
propose that (1) TAS2Rs are a class of proteins regulating uterine contraction and gestational duration, and (2)
TAS2R agonists are broad spectrum tocolytics potentially suitable for PTB management. To test these
hypotheses, we will directly study how bitter tastants activate the TAS2R signaling pathway to relax human
myometrium with pharmacological approaches and siRNA lentiviral expression technology (Aim 1). We will then
use Tas2r deletion mice to determine whether bitter tastants activate TAS2Rs to cause USM relaxation, and
whether the TAS2Rs are critical for maintaining uterine quiescence during pregnancy, setting gestational
duration, in mice (Aim 2). Finally, we will study the effectiveness of bitter tastants in preventing mouse PTB
induced by LPS and RU486, and determine the role of TAS2Rs in bitter tastants' prevention of LPS- or RU486-
induced PTB (Aim 3). This study will uncover the molecular mechanisms by which bitter tastants relax mouse
and human uteri, determine whether the TAS2R family plays a major role in uterine quiescence during pregnancy
and parturition, establish whether the TAS2R family is an attractive therapeutic target for treating PTL in human
pregnancy, and help determine whether bitter tastants can be developed as new and more effect...

## Key facts

- **NIH application ID:** 10428573
- **Project number:** 5R01HD095539-05
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Ronghua ZhuGe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $340,611
- **Award type:** 5
- **Project period:** 2018-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428573

## Citation

> US National Institutes of Health, RePORTER application 10428573, Uterine bitter taste receptors in pregnancy and preterm labor management (5R01HD095539-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10428573. Licensed CC0.

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