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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.

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