The Role of Calcium Homeostasis in Regulating Uterine Contractility and Tone

摘要 预防初次剖腹产是产科护理的中心目标；然而，在美国， 三分之一的分娩是通过剖腹产进行的。剖腹产最常见的指征是功能障碍。 子宫收缩(难产)，其病因仍很不清楚。足月分娩成功 需要子宫平滑肌细胞产生强有力的、持续的和重复的收缩。这个独一无二的 分娩的特点赋予了子宫肌细胞显著的代谢需求。因此，正常的条款 分娩需要同时增加肌层收缩机械和能量生产，以防止 难产。有节奏地释放钙离子存储编码特定的空间和时间属性，提供 调节中间钙依赖过程的细胞指令，包括钙依赖过程 新陈代谢和基因表达。基质相互作用分子1调节细胞内钙稳态 (STIM1)，肌浆/内质网(S/内质网)膜结合钙传感器和Orai1，钙通道 亚基，它们共同构成了存储操作的钙进入(SOCE)途径。STIM1还充当 激活包括钙调神经磷酸酶/核在内的多种下游通路的多功能信号分子 因子激活的T细胞(NFAT)依赖的代谢基因表达。我们研究的长期目标是 确定足月分娩时子宫收缩的机制。这项提案的目标是界定 STIM1-SOCE在分娩子宫肌层中的作用我们的中心假设是STIM1起着钙传感器的作用 并且需要补充S/内质网和线粒体中的钙储存。我们假设STIM1依赖的钙离子 FLOX激活钙调神经磷酸酶/NFAT途径，是代谢灵活性和预防子宫内膜异位症所必需的。 平滑的肌肉疲劳。我们的初步数据提供了强有力的证据，证明STIM1-SOCE钙振荡和 妊娠子宫的正常收缩表型需要依赖于STIM1的代谢信号。这个 我们项目的目标是：1)确定STIM1依赖的钙振荡对子宫肌层的贡献 产程中收缩；2)确定STIM1在调节代谢灵活性和预防子宫收缩中的作用 3)证明代谢激酶MAP4K4作为一种负调节因子 STIM1-SOCE并提供概念证明，即旨在增强STIM1-SOCE的策略可能是有效的 在治疗不正常的分娩方面。这里提出的研究将建立一种新的子宫研究范式 足月分娩时的收缩能力。

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.