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.

项目摘要摘要早产是一个主要的医学问题，导致非常早产的残疾和死亡。治疗方法管理早产劳动是标签外且无效的。当今使用的糖酵解疗法在48小时以上是令人满意的，并且没有FDA批准。早产劳动往往比白人妇女更经常影响非洲裔美国妇女。我们试图了解导致早产和早产的肌层的功能失调的放松出生。我们的中心假设是一氧化氮是由微血管内皮局部在局部内生成的由于机械拉伸并增加了子宫膨胀的血液流动。一氧化氮S-硝酸盐CX43 肌肉细胞。 CX43 S-硝化促进C末端磷酸化，该磷酸化在其半通道状态和有利于肌肉细胞静止。半通道在劳动时形成间隙连接。间隙连接是激活的特征子宫肌。促进连接蛋白43 S-硝化为溶式发展提供了独特的目标。翻译如果我们要发现并利用供应的独特机制，那么人类怀孕组织中的方法至关重要怀孕期间的子宫静止及其在早产的失调。