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Regulation of CAP Protein S-Nitrosation in Preterm Labor

早产中 CAP 蛋白 S-亚硝化的调节

基本信息

批准号：
10221011
负责人：
IAIN L BUXTON
金额：
$ 48.23万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221011
关键词：
Accounting Actins Acute Affect Asthma Biological Assay Biophysics Cavia Contractile Proteins Cyclic GMP Development F-Actin Failure Fingerprint Functional disorder Generations Goals Human In Vitro Infection Length Light MYLK gene Maintenance Measures Mediating Modeling Molecular Morbidity - disease rate Myosin Light Chain Kinase Nature Nitric Oxide Nitric Oxide Donors Nitrosation Oxidoreductase Oxytocin Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Post-Translational Protein Processing Pregnancy Pregnant Women Premature Birth Premature Labor Prevention Protein Dephosphorylation Protein S Proteins Regulation Relaxation Research Resistance Role S-Nitrosoglutathione Signal Transduction Site Smooth Muscle Steroids Testing Therapeutic Tissues Tocolysis Tocolytic Agents Uterine Contraction Uterus Woman antenatal cell motility design experimental study fetal inhibitor/antagonist innovation mortality myometrium myosin phosphatase new therapeutic target novel novel strategies porcine model pregnant prevent profilin 1 protein function telokin treatment strategy

项目摘要

Discovery of the molecular mechanisms subserving human uterine quiescence during pregnancy and their dysregulation in spontaneous preterm labor is the objective of this proposal. We will test the hypothesis that failure of preterm human myometrium to relax to nitric oxide-(NO) is the result of dysregulated S-nitrosation of specific smooth muscle contractile proteins. Our long-term goal is to find new effective tocolytics to treat women who enter labor too soon. Preterm labor leads to preterm delivery, a global problem accounting for 75% of fetal morbidity and mortality. No drugs reliably prevent labor in patients who enter labor preterm, thereby allowing their pregnancies to go to term. Therapeutic approaches to manage spontaneous preterm labor (SPTL) are employed without clear evidence of benefit for acute or maintenance tocolysis. NO-mediated relaxation of myometrium is cGMP-independent. Preterm myometrium fails to relax to NO. Discovering the mechanism of action of S-nitrosated contractile proteins can suggest new therapeutic targets to manage SPTL. We propose that gestational quiescence until term results from regulated post-translational S- nitrosation of myosin light chain kinase (MLCK), the regulatory light chain (MYL9) and profilin-1 (PFN1). Addition of NO relaxes term, but not preterm laboring tissues as a result of S-nitrosation differences that alter the function of these CAPs in SPTL. Discovering the effect of regulated S-nitrosations on the mechanism of contractile protein action in term tissues, term tissues from patients in labor and in SPTL (with controls for gestational timing, tocolytic and antenatal steroid use, infection and gestational length) will establish whether or not NO is an endogenous relaxation signal. Comparison of this S-NO fingerprint with that measured following relaxation of the tissue by NO addition in each pregnancy state is novel because SPTL is not simply early labor, will likely be influenced by infection and/or gestational length and because NO- induced relaxation of spontaneous and oxytocin-induced contractions of preterm myometrium is blunted. S-nitrosation differences between labor and SPTL point to altered quiescence mechanisms. Gestational length comparisons in the guinea pig will establish a model in which to investigate S-nitroso regulation of CAP proteins. We describe innovative experiments employing pregnant guinea pigs and tissues from pregnant women and in vitro functional assays designed to reveal the mechanisms underlying the failure of preterm tissues to relax to NO. Completion of this research will suggest therapeutic strategies for the treatment of SPTL such as the S-nitrosoglutathione reductase that regulates S- nitroso protein levels and is known to provide therapeutic benefit in asthma and for which an inhibitor is in development.

人类妊娠期子宫静止分子机制的发现及其意义自发性早产的调节失调是本提案的目标。我们将检验一个假设，早产人子宫肌层松弛一氧化氮（NO）是由于特定的平滑肌收缩蛋白。我们的长期目标是找到新的有效的宫缩抑制剂来治疗过早进入分娩的妇女。早产导致早产是一个全球性问题，占胎儿发病率和死亡率的75%。没有可靠的药物防止早产患者分娩，从而使其妊娠足月。治疗采用管理自发性早产（SPTL）的方法，但没有明确的证据表明急性或维持性安胎 NO介导的子宫肌层松弛是cGMP非依赖性的。早产子宫肌层不能松弛至NO。发现S-亚硝化收缩蛋白的作用机制可以提出新的治疗靶点，管理SPTL。我们认为，妊娠期静止直到足月是由受调节的翻译后S- 肌球蛋白轻链激酶（MLCK）、调节轻链（MYL 9）和profilin-1（PFN 1）的亚硝化。添加 NO松弛足月分娩组织，但不松弛早产分娩组织，这是由于S-亚硝化差异改变了这些组织的功能。在SPTL中的CAP。发现受调节的S-亚硝化对足月组织收缩蛋白作用机制的影响，来自分娩和SPTL患者的组织（对照妊娠时间，宫缩抑制剂和产前类固醇使用，感染和妊娠时间）将确定NO是否是内源性舒张信号。与此相比， S-NO指纹与测量以下松弛的组织在每个怀孕状态下NO添加是新的因为SPTL不是简单的早产，可能会受到感染和/或妊娠时间的影响，因为NO- 早产子宫肌层的自发和催产素诱导的收缩的诱导松弛减弱。S-亚硝化分娩和SPTL之间的差异表明静息机制的改变。中的几何长度比较豚鼠将建立研究CAP蛋白的S-亚硝基调节的模型。我们描述创新使用怀孕豚鼠和孕妇组织的实验和体外功能测定，揭示早产组织不能松弛至NO的机制。这项研究的完成将提出了治疗SPTL的治疗策略，例如调节S-亚硝基谷胱甘肽还原酶的S-亚硝基谷胱甘肽还原酶。亚硝基蛋白水平，并且已知其在哮喘中提供治疗益处，发展