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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

基本信息

批准号：
10490263
负责人：
Chad A Grotegut
金额：
$ 47.59万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10490263
关键词：
Address Animal Model Biopsy Specimen Birth Calcineurin Calcium Calcium Binding Cell Respiration Cell membrane Cesarean section Characteristics Complex Contracts Data Development Endoplasmic Reticulum Enzymes Etiology Fatigue Frequencies Gene Expression Genes Goals Gravid High Fat Diet Homeostasis Human Impairment Instruction Integral Membrane Protein Labor Dystocia Link MAP2K4 gene Mediating Membrane Metabolic Metabolism Mitochondria Modeling Mus Muscle Cells Muscle Fatigue Myometrial Obesity Oxidoreductase Oxytocin Pathway interactions Periodicity Phenotype Predisposition Pregnancy Prevention Primary Prevention Process Production Property Proteins Regulation Research Role STIM1 gene Signal Transduction Signaling Molecule Smooth Muscle Tissues United States Uterine Contraction Uterus Wild Type Mouse Woman defined contribution design extracellular signal-regulated kinase 4 flexibility inhibitor mouse model myometrium novel novel therapeutics nuclear factors of activated T-cells obstetric care prevent protein expression sensor uterine contractility uterine smooth muscle cell voltage

项目摘要

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.

摘要