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

摘要 每年，全球将有330万婴儿死于妊娠并发症，这些并发症导致 早产(PTB)或死产。尽管进行了大量调查，但目前对其机制的理解 足月和早产仍然有限，危险因素的识别不完整，而且是预防性的。 治疗方法很少。补充孕酮(P)治疗单胎妊娠和 以往的肺结核病史是目前美国预防肺结核的标准护理。然而，我们的 对其行动模式缺乏机械性的理解。宫颈重塑，通过这个过程 宫颈从封闭的刚性结构转变为可打开的顺应性结构，以允许安全通过 胎儿，是正常分娩的关键和基本特征。在人类和小鼠身上，这个过程在早期就开始了。 怀孕了。因此，对这一机制的更好理解有可能为新的早期预防措施提供信息 并提供对当前治疗方法的机械性洞察。基于对缺乏脑白质的小鼠的新发现 蛋白多糖，核心蛋白，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)颈椎机械性功能障碍是由于胶原纤维和弹性纤维的缺陷所致 3)妊娠期间宫颈ECM的结构组织受到精细的控制 黄体酮和雌激素。本研究的目的是确定P和E调节的转录 调控细胞外基质结构、蛋白质周转和机械功能的网络及其机制 通过它，核心蛋白在未怀孕和早孕的宫颈中确保宫颈的能力。最后我们会 用蛋白多糖和大聚糖缺乏的小鼠来检验补充磷可以 修复宫颈的机械功能，从而提供一种补充磷的机制 有利于降低既往有肺结核病史的女性患肺结核的风险。总体来说，拟议的研究是基于 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肺结核的可能性。

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.