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.

项目概要摘要早产是一个重大的医学问题，导致极早产儿残疾和死亡。治疗方法管理早产是标签外且无效的。目前使用的宫缩抑制剂治疗超过 48 小时后均无法令人满意，并且没有一个获得 FDA 批准。早产对非洲裔美国女性的影响比白人女性更常见。我们试图了解导致早产和由此产生的早产的子宫肌层松弛功能失调出生。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流向扩张子宫的血流增加，细胞受到了影响。一氧化氮 S-亚硝酸盐 Cx43 in 肌肉细胞。 Cx43 S-亚硝化促进 C 末端磷酸化，使 Cx43 保持在半通道状态，有利于肌肉细胞静止。半通道在分娩时形成间隙连接。间隙连接是激活的一个特征子宫肌层。促进连接蛋白 43 S-亚硝化为宫缩发育提供了独特的靶点。翻译性如果我们要发现和利用促进人类妊娠组织的独特机制，那么研究人类妊娠组织的方法至关重要妊娠期间子宫静止及其早产时的失调。