# The Role of Calcium Homeostasis in Regulating Uterine Contractility and Tone

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $475,907

## Abstract

ABSTRACT
Prevention of the primary cesarean section is a central goal of obstetrical care; however, in the United States,
one-third of births occur by cesarean delivery. The most common indication for cesarean delivery is dysfunctional
uterine contraction (labor dystocia), the etiology of which remains largely unknown. Successful labor at term
requires uterine smooth muscle cells to generate forceful, sustained, and repetitive contractions. This unique
characteristic of parturition confers a significant metabolic demand on uterine myocytes. Therefore, normal term
labor requires a concurrent increase in both myometrial contractile machinery and energy production to prevent
labor dystocia. Rhythmic release of Ca2+ stores encode specific spatial and temporal properties that provide
cellular instructions for the regulation of intermediate Ca2+-dependent processes, including Ca2+-dependent
metabolism and gene expression. Intracellular Ca2+ homeostasis is regulated by stromal interaction molecule 1
(STIM1), a sarco/endoplasmic reticulum (S/ER) membrane-bound calcium sensor, and Orai1, a Ca2+ channel
subunit, which together comprise the store-operated calcium entry (SOCE) pathway. STIM1 also serves as a
multifunctional signaling molecule by activating a variety of downstream pathways, including calcineurin/nuclear
factor activated T-cells (NFAT)-dependent metabolic gene expression. The long-term goal of our research is to
identify the mechanisms governing uterine contractility in term labor. The objective of this proposal is to define
the role of STIM1-SOCE in the laboring myometrium. Our central hypothesis is that STIM1 acts as a Ca2+ sensor
and is required to refill Ca2+ stores in both the S/ER and the mitochondria. We posit that STIM1-dependent Ca2+
flux activates the calcineurin/NFAT pathway and is required for metabolic flexibility and prevention of uterine
smooth muscle fatigue. Our preliminary data provide strong evidence that STIM1-SOCE Ca2+ oscillations and
STIM1-dependent metabolic signaling are required for a normal contractile phenotype in the gravid uterus. The
goals of our project are to: 1) define the contribution of STIM1-dependent Ca2+ oscillations to myometrial
contraction in labor; 2) determine the role of STIM1 in regulating metabolic flexibility and prevention of uterine
smooth muscle fatigue; and 3) demonstrate that the metabolic kinase MAP4K4 acts as a negative regulator of
STIM1-SOCE and provide proof of concept that strategies designed to augment STIM1-SOCE may be effective
in treating dysfunctional labor. The research proposed here will establish a novel paradigm for uterine
contractility in term labor.

## Key facts

- **NIH application ID:** 10490263
- **Project number:** 5R01HD096385-05
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Chad A Grotegut
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $475,907
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490263

## Citation

> US National Institutes of Health, RePORTER application 10490263, The Role of Calcium Homeostasis in Regulating Uterine Contractility and Tone (5R01HD096385-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10490263. Licensed CC0.

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