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.
/ RELEVANCE Prevention of the primary cesarean section is a critical objective in obstetric care; the leading indication for cesarean delivery in the United States is dysfunctional uterine contraction (labor dystocia). This proposal seeks to better understand normal and abnormal uterine contraction in term labor by studying the role of an intracellular calcium sensor ? stromal interaction molecule 1 (STIM1). Understanding how the smooth muscle of the uterus generates forceful and sustained contractions in labor will aid in development of novel therapies for labor dystocia.