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: 9157750
• 负责人: MALA S. MAHENDROO
• 金额: $ 38.15万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9157750
• 关键词: American; Animal Model; Architecture; Biochemical; Biomechanics; Birth; Cervical; Cervix Uteri; Clinical; Collagen; Collagen Fiber; Collagen Fibril; Congresses; Data; Defect; Detection; Development; Diagnosis; Disease; Early treatment; Elastic Fiber; Elastin; Elastin Fiber; Ensure; Estrogens; Extracellular Matrix; FBN1; Fetus; Fibrillar Collagen; Functional disorder; Genes; Goals; Gynecologist; Hormonal; Human; Hyaluronan; Infection; Intervention; Investigation; Knockout Mice; Knowledge; Leucine; Low Birth Weight Infant; Mechanics; Mediating; Minor; Modality; Molecular; Mus; Mutation; National Institute of Child Health and Human Development; Outcome; Play; Population; Pregnancy; Premature Birth; Premature Labor; Premature Rupture Fetal Membranes; Prevention; Prevention therapy; Preventive therapy; Process; Progesterone; Property; Proteins; Proteoglycan; Proteomics; Recommendation; Recording of previous events; Recurrence; Risk; Risk Factors; Role; Signal Pathway; Structural Genes; Structural defect; Structure; Supplementation; Testing; Therapeutic; Time; Tissues; United States; Uterine Contraction; Woman; base; biglycan; biomarker identification; clinically relevant; crosslink; decorin; effective therapy; fibrillogenesis; hormone regulation; improved; insight; mRNA Expression; novel; pregnant; premature; prevent; protein degradation; protein expression; repaired; standard of care; steroid hormone; stillbirth

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.

抽象的 全球每年有 330 万婴儿死于妊娠并发症，导致 早产（PTB）或死产。尽管进行了大量研究，但目前对机制的了解 足月和早产仍然有限，风险因素的识别不完整，预防性措施 疗法很少。单胎妊娠妇女的补充黄体酮 (P) 治疗 既往 PTB 病史是目前美国预防 PTB 的护理标准。然而，我们的 缺乏对其作用方式的机械理解。宫颈重塑，这个过程 子宫颈从封闭的刚性结构转变为可以打开以允许安全通过的顺应结构 胎儿是正常分娩的一个关键和基本特征。在人类和小鼠中，这个过程开始于早期 怀孕。因此，加深对这一机制的了解有可能为新的早期预防措施提供信息 疗法并提供对当前疗法的机制见解。基于缺乏小鼠的新发现 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) 会导致 颈椎机能不全，2）颈椎机械功能障碍是由于胶原蛋白和弹力纤维同时缺陷造成的 组装和3）妊娠期宫颈ECM的结构组织受到严格控制 黄体酮和雌激素。当前研究的目标是确定 P 和 E 调节的转录 调节 ECM 结构、蛋白质周转和机械功能的网络并探索其机制 核心蛋白聚糖确保非妊娠和早期妊娠子宫颈的宫颈功能。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 P 可以改善这一假设 修复子宫颈的机械功能，从而提供补充 P 的一种机制 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 PTB 临床干预的可能性。