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:
- 金额:$ 48.23万
- 依托单位:
- 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:
- 关键词:AccountingActinsAcuteAffectAsthmaBiological AssayBiophysicsCaviaContractile ProteinsCyclic GMPDevelopmentF-ActinFailureFingerprintFunctional disorderGenerationsGoalsHumanIn VitroInfectionLengthLightMYLK geneMaintenanceMeasuresMediatingModelingMolecularMorbidity - disease rateMyosin Light Chain KinaseNatureNitric OxideNitric Oxide DonorsNitrosationOxidoreductaseOxytocinPathway interactionsPatientsPharmaceutical PreparationsPhosphorylationPost-Translational Protein ProcessingPregnancyPregnant WomenPremature BirthPremature LaborPreventionProtein DephosphorylationProtein SProteinsRegulationRelaxationResearchResistanceRoleS-NitrosoglutathioneSignal TransductionSiteSmooth MuscleSteroidsTestingTherapeuticTissuesTocolysisTocolytic AgentsUterine ContractionUterusWomanantenatalcell motilitydesignexperimental studyfetalinhibitor/antagonistinnovationmortalitymyometriummyosin phosphatasenew therapeutic targetnovelnovel strategiesporcine modelpregnantpreventprofilin 1protein functiontelokintreatment 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.
妊娠期子宫静止的分子机制及其机制的发现
自发早产的调节失调是这项提议的目标。我们将检验失败的假设
早产儿子宫肌层向一氧化氮(NO)的松弛是S亚硝化作用失调的结果
平滑肌收缩蛋白。
我们的长期目标是找到新的有效的生育药物来治疗过早分娩的妇女。早产先兆
早产是一个全球性的问题,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,从而使他们的怀孕进入足月。治疗性的
自发性早产(SPTL)的管理方法在没有明确证据表明对急性早产有好处的情况下使用
或维持性发酵症。
NO介导的子宫肌层松弛不依赖cGMP。早产子宫肌层未能松弛至NO。
发现S亚硝化收缩蛋白的作用机制可为临床治疗提供新的靶点
管理SPTL。我们认为,妊娠期停顿到足月是由受管制的翻译后S-
亚硝化肌球蛋白轻链激酶(MLCK)、调节轻链(MYL9)和Profilin-1(PFN1)。添加
NO可松弛足月分娩组织,但不能松弛早产组织,这是由于S-亚硝化作用的差异改变了这些组织的功能
SPTL中的CAPS。
发现调节的S亚硝化作用对足月组织收缩蛋白作用机制的影响
来自分娩患者和SPTL患者的组织(对妊娠时机、宫缩和产前类固醇使用进行控制,
感染和妊娠长度)将确定NO是否是内源性松弛信号。比较一下这个
S--在每种妊娠状态下,通过不添加添加剂而测量到的组织松弛后没有指纹是新的
因为SPTL不是简单的早产,可能会受到感染和/或妊娠长度的影响,因为没有-
自发性和催产素引起的早产子宫肌层收缩的诱导松弛被钝化。S-亚硝化
分娩和SPTL之间的差异表明静止机制发生了变化。孕妇的妊娠长度比较
豚鼠将建立S-亚硝基对CAP蛋白调节的模型。我们描述了创新的
利用怀孕豚鼠和孕妇组织进行的实验和体外功能分析
目的:揭示早产组织不能松弛至NO的机制。完成这项研究将
提出治疗的策略,如S-亚硝基谷胱甘肽还原酶调节S-
亚硝基蛋白水平,已知对哮喘有治疗作用,目前有一种抑制药
发展。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Novel Tocolytic Strategy: Modulating Cx43 Activity by S-Nitrosation.
- DOI:10.1124/jpet.120.000427
- 发表时间:2021-03
- 期刊:
- 影响因子:0
- 作者:Barnett SD;Asif H;Anderson M;Buxton ILO
- 通讯作者:Buxton ILO
Evolution of Medical Approaches and Prominent Therapies in Breast Cancer.
- DOI:10.3390/cancers14102450
- 发表时间:2022-05-16
- 期刊:
- 影响因子:5.2
- 作者:Duan, Suzann;Buxton, Iain L. O.
- 通讯作者:Buxton, Iain L. O.
β3 Receptor Signaling in Pregnant Human Myometrium Suggests a Role for β3 Agonists as Tocolytics.
- DOI:10.3390/biom13061005
- 发表时间:2023-06-17
- 期刊:
- 影响因子:5.5
- 作者:
- 通讯作者:
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{{ truncateString('IAIN L BUXTON', 18)}}的其他基金
Post-translational Modification of Cx43 Regulates Myometrial Quiescence
Cx43 的翻译后修饰调节子宫肌层静止
- 批准号:
10575364 - 财政年份:2023
- 资助金额:
$ 48.23万 - 项目类别:
Regulation of CAP Protein S-Nitrosation in Preterm Labor
早产中 CAP 蛋白 S-亚硝化的调节
- 批准号:
10002335 - 财政年份:2018
- 资助金额:
$ 48.23万 - 项目类别:
REGULATION OF MYOMETRIAL RELAXATION: AGONIST-SPECIFIC cGMP ACTION
子宫肌层松弛的调节:激动剂特异性 cGMP 作用
- 批准号:
8138103 - 财政年份:2010
- 资助金额:
$ 48.23万 - 项目类别:
REGULATION OF MYOMETRIAL RELAXATION: AGONIST-SPECIFIC cGMP ACTION
子宫肌层松弛的调节:激动剂特异性 cGMP 作用
- 批准号:
7599726 - 财政年份:2007
- 资助金额:
$ 48.23万 - 项目类别:
REGULATION OF MYOMETRIAL RELAXATION: AGONIST-SPECIFIC cGMP ACTION
子宫肌层松弛的调节:激动剂特异性 cGMP 作用
- 批准号:
7781360 - 财政年份:2007
- 资助金额:
$ 48.23万 - 项目类别:
REGULATION OF MYOMETRIAL RELAXATION: AGONIST-SPECIFIC cGMP ACTION
子宫肌层松弛的调节:激动剂特异性 cGMP 作用
- 批准号:
8044194 - 财政年份:2007
- 资助金额:
$ 48.23万 - 项目类别:
REGULATION OF MYOMETRIAL RELAXATION: AGONIST-SPECIFIC cGMP ACTION
子宫肌层松弛的调节:激动剂特异性 cGMP 作用
- 批准号:
7201882 - 财政年份:2007
- 资助金额:
$ 48.23万 - 项目类别:
REGULATION OF MYOMETRIAL RELAXATION: AGONIST-SPECIFIC cGMP ACTION
子宫肌层松弛的调节:激动剂特异性 cGMP 作用
- 批准号:
7369765 - 财政年份:2007
- 资助金额:
$ 48.23万 - 项目类别:
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