The Role of Calcium Homeostasis in Regulating Uterine Contractility and Tone

钙稳态在调节子宫收缩力和张力中的作用

• 批准号: 10480126
• 负责人: Chad A Grotegut
• 金额: $ 32.39万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480126
• 关键词: Role; Calcium; Homeostasis; Regulating; Uterine

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.

抽象的 预防初次剖宫产是产科护理的核心目标；然而，在美国， 三分之一的分娩是通过剖腹产进行的。剖宫产最常见的指征是功能障碍 子宫收缩（分娩难产），其病因尚不清楚。足月成功分娩 需要子宫平滑肌细胞产生有力、持续和重复的收缩。这种独特的 分娩的特征对子宫肌细胞提出了显着的代谢需求。因此，正常术语 分娩需要同时增加子宫肌层收缩机制和能量产生，以防止 难产。 Ca2+ 储存的有节奏释放编码特定的空间和时间特性，提供 用于调节中间 Ca2+ 依赖性过程（包括 Ca2+ 依赖性）的细胞指令 代谢和基因表达。细胞内 Ca2+ 稳态由基质相互作用分子 1 调节 (STIM1)，一种肌浆/内质网 (S/ER) 膜结合钙传感器，以及 Orai1，一种 Ca2+ 通道 亚基，共同组成钙池操纵的钙进入（SOCE）途径。 STIM1 还用作 通过激活多种下游途径（包括钙调神经磷酸酶/核）的多功能信号分子 因子激活 T 细胞 (NFAT) 依赖性代谢基因表达。我们研究的长期目标是 确定足月分娩时控制子宫收缩的机制。该提案的目标是定义 STIM1-SOCE 在临产子宫肌层中的作用。我们的中心假设是 STIM1 充当 Ca2+ 传感器 需要补充 S/ER 和线粒体中的 Ca2+ 储备。我们假设 STIM1 依赖的 Ca2+ Flux 激活钙调神经磷酸酶/NFAT 通路，是代谢灵活性和预防子宫肌瘤所必需的。 平滑肌疲劳。我们的初步数据提供了强有力的证据，表明 STIM1-SOCE Ca2+ 振荡和 STIM1 依赖性代谢信号是妊娠子宫正常收缩表型所必需的。这 我们项目的目标是：1) 定义 STIM1 依赖性 Ca2+ 振荡对子宫肌层的贡献 临产收缩； 2）确定STIM1在调节代谢灵活性和预防子宫肌瘤中的作用 平滑肌疲劳； 3) 证明代谢激酶 MAP4K4 作为负调节因子 STIM1-SOCE 并提供概念证明，证明旨在增强 STIM1-SOCE 的策略可能是有效的 治疗功能失调性劳动。这里提出的研究将为子宫建立一个新的范例 足月劳动的收缩性。