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 每年，由于怀孕并发症导致的并发症，每年330万婴儿将死亡 早产（PTB）或死产。尽管进行了大量调查，但目前对 术语和早产分娩仍然有限，风险因素的识别是不完整的，预防性 疗法很少。单胎怀孕的女性的补充孕酮（P）疗法 PTB的先前历史目前是预防美国PTB的护理标准。但是，我们的 对其作用方式的机械理解是不存在的。宫颈重塑，该过程 子宫颈从封闭的刚性结构转变为合规结构，该结构可以打开以允许安全通过 胎儿是正常分娩的关键和重要特征。在人和老鼠中，这个过程始于早期 怀孕。因此，对这种机制的理解有所提高，有可能告知新的早期预防措施 疗法并提供有关当前疗法的机械洞察力。根据小鼠的新发现，缺乏 蛋白聚糖，Decorin，我们提供的证据表明1）宫颈功能失调的细胞外基质（ECM）导致 宫颈功能不全，2）颈椎机械功能障碍是由于胶原蛋白和弹性纤维的缺陷而引起的 组装和3）妊娠中宫颈ECM的结构组织由精美控制 孕酮和雌激素。当前研究的目的是确定P和E调节的转录 调节ECM结构，蛋白质更新和机械功能的网络并探索机制 Decorin确保了非怀孕和早期怀孕子宫颈的颈能力。最后我们会的 使用缺乏蛋白聚糖蛋白和大型群体的小鼠测试P补充P可以 修复子宫颈的机械功能，因此提供了一种补充P的机制 有益于降低先前PTB女性PTB的风险。基于 引人入胜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。