The Role of Calcium Homeostasis in Regulating Uterine Contractility and Tone

摘要 预防初次剖宫产是产科护理的中心目标;然而，在美国， 三分之一的分娩是剖腹产。剖宫产最常见的指征是功能障碍 子宫收缩（难产），其病因仍在很大程度上未知。足月产程成功 需要子宫平滑肌细胞产生有力的、持续的和重复的收缩。这种独特 分娩的特征赋予子宫肌细胞显著的代谢需求。因此，正常术语 分娩需要子宫肌层收缩机制和能量产生的同时增加， 难产Ca 2+商店的节律性释放编码特定的空间和时间特性， 调节中间Ca 2+依赖过程的细胞指令，包括Ca 2+依赖过程， 代谢和基因表达。基质相互作用分子1调控细胞内钙稳态 （STIM 1），一种肌/内质网（S/ER）膜结合的钙传感器，和Orai 1，一种Ca 2+通道 亚基，其共同构成钙库操纵的钙进入（SOCE）途径。STIM 1也可用作 通过激活多种下游途径，包括钙调神经磷酸酶/核 因子活化的T细胞（NFAT）依赖性代谢基因表达。我们研究的长期目标是 确定足月分娩子宫收缩力的机制。本提案的目的是确定 STIM 1-SOCE在分娩子宫肌层中的作用。我们的中心假设是STIM 1作为Ca 2+传感器 并且需要补充S/ER和线粒体中的Ca 2+储存。我们证实，STIM 1依赖的Ca 2 + 通量激活钙调神经磷酸酶/NFAT通路，是代谢灵活性和预防子宫内膜异位症所必需的。 平滑肌疲劳我们的初步数据提供了强有力的证据表明，STIM 1-SOCE钙振荡和 STIM 1依赖性代谢信号是妊娠子宫正常收缩表型所必需的。的 我们的项目的目标是：1）确定STIM 1依赖性Ca 2+振荡对子宫肌层的贡献， 2）确定STIM 1在调节代谢灵活性和预防子宫收缩中的作用 平滑肌疲劳;和3）证明代谢激酶MAP 4K 4作为负调节剂， STIM 1-SOCE，并提供旨在增强STIM 1-SOCE的策略可能有效的概念证明 治疗功能失调性分娩本文提出的研究将为子宫内膜异位症建立一个新的范式， 足月分娩的收缩力。

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.