Monitoring Changes in Cervical Microstructure During Pregnancy

描述(申请人提供)：正常妊娠的一个重要部分是宫颈重塑，通过这个过程，胶原微结构在整个怀孕期间解体，宫颈软化，从而最终分娩胎儿。时机决定一切；错误会导致早产或早产，这两种情况都代价高昂，而且病态。值得注意的是，目前还没有工具来客观地量化这些变化，这使得临床医生没有手段来准确确定风险，甚至没有语言来准确地沟通患者的宫颈状况。这项拟议工作的主要目标是进一步开发和测试技术，以客观地描述和量化宫颈微观结构的胶原排列和软化。第二个目标是建立一种非人灵长类动物(NHP)模型，用于研究妊娠期宫颈重塑。我们的初步研究表明，两种定量超声技术可以准确地评估微结构组织和柔软度的变化：波束导向定量超声(QUS)和声辐射力脉冲(ARFI)。在这项拟议的工作中，我们将使用这些技术来研究NHP患者正常怀孕期间宫颈的微结构变化。有两个分支：第一个分支涉及子宫切除标本，第二个分支是活的NHP。对于前者，我们将为无关的研究项目研究被安乐死的动物的正常标本。其中一半的人将在引产前使用一种临床上用来使宫颈成熟的药物进行宫颈成熟，另一半人将不接受治疗。我们将对这两组患者的声学散射特性(用于描述胶原结构)和组织柔软度的定量超声测量进行比较，并将使用非线性光学显微镜(用于成像胶原)来证实超声结果。(这一比较与对人类受试者子宫切除标本进行的类似研究相似。)另一个分支是对正常月经期间几个时间点的定量超声参数进行一系列研究(以确定潜在的生物变异性)，然后是正常妊娠(以描述怀孕期间的胶原重组和宫颈软化)。一个成功的NHP孕期宫颈成熟模型将显著增加有关宫颈的知识体系，并加速向活体人类研究的过渡。最终，对妊娠中宫颈变化的全面了解可以帮助：(A)选择合适的过期引产对象；(B)预测早产风险最高的患者；(C)监测早产或过期成熟失败的治疗方法；以及(D)基于对导致宫颈异常重塑的特定微观结构变化的彻底了解，通过有针对性地研究相关分子事件，开发早产和过期产的创新治疗策略。

DESCRIPTION (provided by applicant): An essential part of normal pregnancy is cervical remodeling, the process by which the collagen microstructure disorganizes and the cervix softens throughout pregnancy to allow eventual delivery of a fetus. Timing is everything; errors result in preterm or post-dates birth, both of which are costly and morbid. Remark- ably, there are currently no tools to objectively quantify these changes, leaving clinicians without a means to precisely determine risk or even a language to accurately communicate the status of a patient's cervix. The primary objective of this proposed effort is to further develop and test technology to objectively describe and quantify cervical microstructural collagen arrangement and softening. A secondary objective is to establish a nonhuman primate (NHP) model for the study of cervical remodeling in pregnancy. Our preliminary studies suggest that two quantitative ultrasound techniques can accurately assess changes in microstructural organization and softness: quantitative ultrasound with beamsteering (QUS) and acoustic radiation force impulse (ARFI). Within this proposed effort we will use these techniques to study the microstructural changes that the cervix undergoes during normal pregnancy in NHPs. There are two branches: the first involves hysterectomy specimens and the second live NHPs. For the former, we will study normal specimens from animals being euthanized for unrelated research projects. Half of the group will undergo cervical ripening with a drug used clinically to ripen the cervix prior to induction of labor, and half will receive no treatment. Quantitative ultrasound measurements of acoustic scattering properties (to describe collagen structure) and tissue softness will be compared in these two groups, and nonlinear optical microscopy (for imaging collagen) will be used to corroborate the ultrasound findings. (This comparison parallels that underway in similar studies of human subject hysterectomy specimens.) The other branch will be a serial study of quantitative ultrasound parameters at several time points throughout normal menstruation (to establish underlying biological variability), and then normal pregnancy (to describe collagen reorganization and cervical softening in pregnancy). A successful NHP model of cervical ripening in pregnancy would add significantly to the body of knowledge about the cervix and accelerate transition to in vivo human studies. Ultimately, a comprehensive understanding of cervical change in pregnancy could allow (a) selection of appropriate candidates for post-dates induction of labor, (b) prediction of patients at greatest risk for preterm delivery, (c) monitorin of treatments for preterm birth or failed post-dates ripening, and most importantly, (d) development of innovative therapeutic strategies for both preterm and post-dates birth via targeted investigation of associated molecular events based on thorough understanding of specific microstructural changes that lead to abnormal cervical remodeling.