Mechanisms by which steroid hormones modulate cervical extracellular matrix structure and function during pregnancy and provide therapeutic protection against preterm birth

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 缺乏对其作用模式的机械理解。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。

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.