Mechanisms by which steroid hormones modulate cervical extracellular matrix structure and function during pregnancy and provide therapeutic protection against preterm birth
类固醇激素在怀孕期间调节宫颈细胞外基质结构和功能并提供针对早产的治疗保护的机制
基本信息
- 批准号:9157750
- 负责人:
- 金额:$ 38.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AmericanAnimal ModelArchitectureBiochemicalBiomechanicsBirthCervicalCervix UteriClinicalCollagenCollagen FiberCollagen FibrilCongressesDataDefectDetectionDevelopmentDiagnosisDiseaseEarly treatmentElastic FiberElastinElastin FiberEnsureEstrogensExtracellular MatrixFBN1FetusFibrillar CollagenFunctional disorderGenesGoalsGynecologistHormonalHumanHyaluronanInfectionInterventionInvestigationKnockout MiceKnowledgeLeucineLow Birth Weight InfantMechanicsMediatingMinorModalityMolecularMusMutationNational Institute of Child Health and Human DevelopmentOutcomePlayPopulationPregnancyPremature BirthPremature LaborPremature Rupture Fetal MembranesPreventionPrevention therapyPreventive therapyProcessProgesteronePropertyProteinsProteoglycanProteomicsRecommendationRecording of previous eventsRecurrenceRiskRisk FactorsRoleSignal PathwayStructural GenesStructural defectStructureSupplementationTestingTherapeuticTimeTissuesUnited StatesUterine ContractionWomanbasebiglycanbiomarker identificationclinically relevantcrosslinkdecorineffective therapyfibrillogenesishormone regulationimprovedinsightmRNA Expressionnovelpregnantprematurepreventprotein degradationprotein expressionrepairedstandard of caresteroid hormonestillbirth
项目摘要
ABSTRACT
On an annual basis 3.3 million babies will die worldwide due to complications in pregnancy that leads to
preterm birth (PTB) or stillbirths. Despite much investigation, the current understanding of the mechanisms of
term and preterm parturition remains limited, the identification of risk factors is incomplete, and preventative
therapies are few. Supplemental progesterone (P) therapy in women with a singleton pregnancy and a
previous history of PTB is currently the standard of care to prevent PTB in the United States. Yet, our
mechanistic understanding of its mode of action is absent. Cervical remodeling, the process by which the
cervix transforms from a closed rigid structure to a compliant structure that can open to allow safe passage of
the fetus, is a key and essential feature of normal parturition. In human and mice, this process begins in early
pregnancy. Thus improved understanding of this mechanism has the potential to inform new early preventative
therapies and provide mechanistic insight into current therapies. Based on novel findings in mice lacking the
proteoglycan, decorin, we provide evidence that 1) a dysfunctional cervical extracellular matrix (ECM) leads to
cervical insufficiency, 2) cervical mechanical dysfunction results from defects in both collagen and elastic fiber
assembly and 3) structural organization of the cervical ECM in pregnancy is under exquisite control by
progesterone and estrogen. The goal of the current study is to identify the P and E regulated transcriptional
networks that regulate ECM structure, protein turnover and mechanical function and to explore the mechanism
by which decorin ensures cervical competency in the nonpregnant and early pregnant cervix. Finally we will
use mice deficient in the proteoglycans decorin and biglycan to test the hypothesis that P supplementation can
repair mechanical function of the cervix and thus provide one mechanism by which P supplementation is
beneficial in reducing risk of PTB in women with a previous PTB. Collectively the proposed studies, based on
compelling preliminary data, has the potential to both expand our understanding of basic mechanisms in
parturition as well as expand the possibilities for clinical intervention in PTB.
摘要
全球每年将有330万婴儿死于妊娠并发症,
早产(PTB)或死产。尽管进行了大量研究,但目前对
足月分娩和早产仍然有限,风险因素的识别不完整,预防性
治疗方法很少。单胎妊娠妇女补充孕酮(P)治疗
在美国,PTB既往史是预防PTB的标准治疗。但我们的
对其作用方式缺乏机械性的理解。子宫颈重塑,
子宫颈从封闭的刚性结构转变为顺应性结构
胎儿,是正常分娩的关键和基本特征。在人类和小鼠中,这一过程始于早期,
怀孕因此,对这一机制的进一步了解有可能为新的早期预防措施提供信息。
治疗,并提供对当前治疗的机制见解。基于在缺乏这种基因的小鼠中的新发现,
蛋白聚糖,核心蛋白聚糖,我们提供的证据表明:1)功能失调的宫颈细胞外基质(ECM)导致
颈椎功能不全,2)胶原和弹性纤维缺陷导致颈椎机械功能障碍
3)妊娠期宫颈ECM的结构组织受到以下因素的精确控制:
孕酮和雌激素。本研究的目的是鉴定P和E调控的转录
调节ECM结构、蛋白质周转和机械功能的网络,并探讨其机制
核心蛋白聚糖通过其确保非妊娠和早期妊娠子宫颈的子宫颈能力。最后我们将
使用缺乏蛋白聚糖核心蛋白聚糖和双糖链蛋白聚糖的小鼠来检验补充磷可以
修复子宫颈的机械功能,从而提供一种补充磷的机制,
有益于降低既往患有PTB的女性患PTB的风险。总体而言,拟议的研究,基于
令人信服的初步数据,有可能扩大我们对基本机制的理解,
分娩以及扩大临床干预PTB的可能性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MALA S. MAHENDROO其他文献
MALA S. MAHENDROO的其他文献
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{{ truncateString('MALA S. MAHENDROO', 18)}}的其他基金
Functional and Molecular Characterization of Epithelial Subtypes in Cervical Remodeling and Preterm Birth
宫颈重塑和早产中上皮亚型的功能和分子特征
- 批准号:
10681015 - 财政年份:2023
- 资助金额:
$ 38.15万 - 项目类别:
Molecular and Mechanical Investigations to Define Collagen and Elastic Fiber Homeostasis in Cervical Remodeling During a Term and Preterm Pregnancy
定义足月和早产期间宫颈重塑中胶原蛋白和弹性纤维稳态的分子和力学研究
- 批准号:
10752526 - 财政年份:2023
- 资助金额:
$ 38.15万 - 项目类别:
Genomic Consequences of Estrogen Receptor Activation in the Cervix
子宫颈雌激素受体激活的基因组后果
- 批准号:
10204064 - 财政年份:2017
- 资助金额:
$ 38.15万 - 项目类别:
Mechanisms by which steroid hormones modulate cervical extracellular matrix structure and function during pregnancy and provide therapeutic protection against preterm birth
类固醇激素在怀孕期间调节宫颈细胞外基质结构和功能并提供针对早产的治疗保护的机制
- 批准号:
9754844 - 财政年份:2016
- 资助金额:
$ 38.15万 - 项目类别:
Mechanisms by which steroid hormones modulate cervical extracellular matrix structure and function during pregnancy and provide therapeutic protection against preterm birth
类固醇激素在怀孕期间调节宫颈细胞外基质结构和功能并提供针对早产的治疗保护的机制
- 批准号:
9982389 - 财政年份:2016
- 资助金额:
$ 38.15万 - 项目类别:
Mechanisms of Cervical Epithelial Barrier Protection Against Ascending Infection and Preterm Birth
宫颈上皮屏障预防上行感染和早产的机制
- 批准号:
10063455 - 财政年份:2016
- 资助金额:
$ 38.15万 - 项目类别:
Mechanisms by which steroid hormones modulate cervical extracellular matrix structure and function during pregnancy and provide therapeutic protection against preterm birth
类固醇激素在怀孕期间调节宫颈细胞外基质结构和功能并提供针对早产的治疗保护的机制
- 批准号:
9334281 - 财政年份:2016
- 资助金额:
$ 38.15万 - 项目类别:
Mechanisms of infection-mediated cervical ripening
感染介导的宫颈成熟机制
- 批准号:
9252296 - 财政年份:2016
- 资助金额:
$ 38.15万 - 项目类别:
REGULATION AND FUNCTION OF HYALURONAN IN CERVICAL REMODELING
透明质酸在宫颈重塑中的调节和功能
- 批准号:
7555046 - 财政年份:2007
- 资助金额:
$ 38.15万 - 项目类别:
Project 3 REGULATION AND FUNCTION OF HYALURONAN
项目3 透明质酸的调控与功能
- 批准号:
6896286 - 财政年份:2004
- 资助金额:
$ 38.15万 - 项目类别:
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