Monitoring Changes in Cervical Microstructure During Pregnancy

描述（由申请人提供）：正常妊娠的一个重要部分是宫颈重塑，在整个妊娠期间，胶原微结构破坏和宫颈软化的过程使胎儿最终能够娩出。时机就是一切；错误导致早产或产后，这两种情况都是昂贵和病态的。值得注意的是，目前还没有客观量化这些变化的工具，这使得临床医生没有精确确定风险的手段，甚至没有一种语言来准确地传达患者宫颈的状态。本研究的主要目的是进一步开发和测试技术，以客观地描述和量化颈椎微结构胶原蛋白的排列和软化。第二个目标是建立一个非人灵长类动物（NHP）模型，用于研究妊娠期颈椎重塑。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）。在这项提议的努力中，我们将使用这些技术来研究nps正常妊娠期间子宫颈的微观结构变化。有两个分支：第一个涉及子宫切除术标本，第二个涉及活的NHPs。对于前者，我们将研究为不相关的研究项目而被安乐死的动物的正常标本。一半的人将在引产前使用临床使用的药物进行宫颈成熟，另一半人将不接受任何治疗。定量超声测量声散射特性（用于描述胶原结构）和组织柔软度将在这两组中进行比较，非线性光学显微镜（用于成像胶原）将用于证实超声结果。（这种比较与正在进行的人类受试者子宫切除术标本的类似研究相似。）另一个分支将是在正常月经期间的几个时间点进行定量超声参数的系列研究（以建立潜在的生物学变异性），然后是正常妊娠（以描述妊娠期间胶原蛋白重组和颈椎软化）。一个成功的妊娠期子宫颈成熟的NHP模型将大大增加关于子宫颈的知识体系，并加速向体内人体研究的过渡。最终，对妊娠期宫颈变化的全面了解可以允许(a)选择合适的产后引产候选人，(b)预测早产风险最大的患者，(c)监测早产或产后成熟失败的治疗，最重要的是，(d)基于对导致宫颈重构异常的特定微观结构变化的透彻理解，通过对相关分子事件的针对性研究，开发针对早产和产后的创新治疗策略。

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.