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Post-translational Modification of Cx43 Regulates Myometrial Quiescence

Cx43 的翻译后修饰调节子宫肌层静止

基本信息

批准号：
10575364
负责人：
IAIN L BUXTON
金额：
$ 21.99万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10575364
关键词：
Acute Affect African American African American population Agonist Birth Blood flow C-terminal Caucasians Cells Cessation of life Connexin 43 Coupling Cyclic AMP Cyclic GMP Cysteine Cytosol Development Disparate Dose Limiting Ethnic Origin FDA approved Fetus Functional disorder Future Gap Junctions Generations Giant Cells Hour Human Label Labor Onset Link Maintenance Measures Mechanics Mediating Medical Membrane Methods Modification Mothers Muscle Cells Muscle relaxation phase Mutate Mutation Myometrial Nitric Oxide Nitrosation Outcome Outcomes Research Oxidoreductase Pathway interactions Pharmaceutical Preparations Pharmacology Phosphorylation Positioning Attribute Post-Translational Protein Processing Post-Translational Regulation Pregnancy Pregnant Uterus Pregnant Women Premature Birth Premature Infant Premature Labor Property Protein Kinase Regulation Relaxation Research Risk Role S-Nitrosoglutathione Serine Site Smooth Muscle Smooth Muscle Myocytes Stretching Terbutaline Testing Therapeutic Time Tissues Tocolysis Tocolytic Agents Uterus Vascular Endothelial Cell Woman disability extreme prematurity gap junction channel health disparity innovation interest monolayer mutant myometrium novel overexpression pharmacologic pregnant prevent protein expression protein kinase C epsilon response translational approach uterine smooth muscle cell

项目摘要

PROJECT SUMMARY ABSTRACT Preterm birth is a major medical problem resulting in disability and death for very preterm infants. Therapeutic approaches to manage preterm labor are off-label and ineffective. No tocolytic therapy in use today is satisfactory beyond 48 hours, and none are FDA approved. Preterm labor more often impacts African American women than their Caucasian counterparts. We seek to understand the dysfunctional relaxation of the myometrium that leads to preterm labor and resulting preterm birth. Our central hypothesis is that nitric oxide is generated locally within the myometrium by microvascular endothelial cells as a result of mechanical stretch and increased blood flow to the expanding uterus. Nitric oxide S-nitrosates Cx43 in the muscle cell. Cx43 S-nitrosation promotes C-terminal phosphorylation that holds Cx43 in its hemichannel state and favors muscle cell quiescence. Hemichannels form gap junctions at the time of labor. Gap junctions are a feature of activated myometrium. Promoting connexin 43 S-nitrosation offers a unique target for tocolytic development. Translational approaches in human pregnancy tissues are essential if we are to discover and exploit the unique mechanisms that subserve uterine quiescence during pregnancy and their dysregulation in preterm labor.

项目摘要早产是导致非常早产儿残疾和死亡的主要医学问题。治疗方法治疗早产的药物都是标签外的，无效的。目前使用的宫缩抑制疗法在48小时以上都不能令人满意，没有一个是FDA批准的。早产更经常影响非洲裔美国妇女比他们的白人同行。我们试图了解子宫肌层松弛功能失调导致早产和由此导致的早产出生我们的中心假设是，一氧化氮是由微血管内皮细胞在子宫肌层局部产生的。由于机械拉伸和增加的血液流向扩张的子宫，一氧化氮S-亚硝化Cx43 肌肉细胞。Cx43 S-亚硝化促进C-末端磷酸化，使Cx43保持在其半通道状态，有利于肌肉细胞静止半通道在分娩时形成缝隙连接。缝隙连接是一种激活的子宫肌层促进连接蛋白43 S-亚硝化为宫缩抑制发育提供了独特的靶点。平移如果我们要发现和利用这种独特的机制，妊娠期子宫静止和早产时的失调。