A Multi-Modality, Multi-Scale Approach to Understanding Parturition

项目摘要 美国的早产率正在上升，据估计，如果所有孕妇都接受了筛查和提供 适当的可用干预措施，95%的肺结核仍将发生，2这都表明我们已经筋疲力尽 所有目前可用的选择和fl反映了我们对这一现象背后的分子机制知之甚少 影响世界每一个社会的复杂而普遍的问题。来自我们实验室的最新fi结果挑战 妊娠期宫颈重塑的现有范例。他们提出，也许分娩前的成熟是 不是简单地加速或加强从受孕后开始逐渐发生的软化 通过交付，而是由完全不同的机制驱动，可能是由次要的ECM组件和/或 非ECM组件，其中一些可能仍未被fi识别。我们开始怀疑胶原蛋白 在ECM达到一个点后，尽管宫颈持续软化和丢失，但它不会进一步重新排列 非细胞外基质成分(如血管)在fi中起着不可忽视的作用。这些fi标识暗示 一种引人注目的宫颈重塑的替代范式，但更重要的是，它们揭示了一个巨大的知识缺口 在我们对分娩的一般理解中。我们的目标是解决这一差距，并探索这一潜在的新 范式，通过构建描述结构-功能关系的患者-特定fic生物力学模型 宫颈和其他支持胎儿的组织(膜，子宫)，基于特殊的fic测量 每个个体的宫颈显微结构和母体解剖。我们还将探索潜在的贡献 宫颈重塑的次要细胞外基质(ECM)和非ECM信息者。为此，我们将使用我们的 恒河猴组织微结构特性和母体解剖的纵向测量模型 在整个怀孕期间使用超声，制定并验证超声参数之间的关系 在体外妊娠计时样本中，探索宫颈组织材料特性之间的关系 子宫、子宫和胎膜的组织生化成分和材料特性 活体样本，并计算每个组织应力和拉伸的精确大小和区域分布 猕猴利用finite元素分析直接获得其个体显微组织和解剖学信息 属性。基本模型将具有足够的fl伸缩性，最终可以容纳其他潜在的贡献者 以宫颈重塑为主，如次要的ECM因素，或非ECM因素。为此，我们将在 我们目前的R01的成功之处在于通过扩展我们的恒河猴模型来深入探讨颈椎之间的关系 显微结构和母体解剖，并寻找宫颈生物力学特性之间的相关性 以及fl对微小的细胞外基质和非细胞外基质成分的宫颈重塑的潜在作用。最终，我们设想 一种结合了成像和生物标记物的建模工具，可全面了解 个人怀孕，这将允许预测出生时间，甚至可能暴露治疗目标 不正常的(早产或推迟的)时间安排。

Project Summary The U.S. preterm birth rate is increasing1 and it estimated that if all pregnant women were screened and offered appropriate available intervention, 95% of PTB would still occur,2 which both indicates that we have exhausted all currently available options and reflects our poor understanding of the molecular mechanisms underlying this complex and common problem that affects every society in the world. Recent findings from our labs challenge the existing paradigm of cervical remodeling in pregnancy. They suggest that perhaps ripening just prior to delivery is not a simple acceleration or enhancement of the softening that occurs progressively from just after conception through delivery, but rather is driven by entirely different mechanisms, perhaps by minor ECM components and/or non-ECM components, some of which are likely still unidentified. We have come to suspect that the collagen in the ECM reaches a point after which it rearranges no further, despite continued cervical softening and loss of strength, and that non-ECM components (e.g. blood vessels) play a significant role. These findings hint at a compelling alternative paradigm for cervical remodeling, but even more, they reveal a large knowledge gap in our understanding of parturition in general. Our goal is to address this gap, and explore this potential new paradigm, by constructing patient-specific biomechanical models that delineate the structure-function relationship of the cervix and other tissues that support the fetus (membranes, uterus), based on specific measurements of cervical microstructure and maternal anatomy in each individual. We will also explore the contribution of potential minor extracellular matrix (ECM) and non-ECM informants of cervical remodeling. To this end, we will use our Rhesus macaque model to longitudinally measure in vivo tissue microstructural properties and maternal anatomy throughout pregnancy using ultrasound, formulate and validate relationships between ultrasound parameters and tissue material properties for the cervix in ex vivo gestation-timed samples, explore relationships between tissue biochemical composition and material properties for the cervix, uterus, and fetal membranes using the ex vivo samples, and calculate the precise magnitude and regional distribution of tissue stress and stretch for each macaque using finite element analysis directly informed by her individual microstructural tissue and anatomical properties. The fundamental model will be flexible enough to eventually accommodate other potential contributors to cervical remodeling, such as minor ECM factors, or non-ECM factors. To this end, we will build upon the successes of our current R01 by expanding our Rhesus model to deeply explore the relationship between cervical microstructure and maternal anatomy, and search for correlations between biomechanical properties of the cervix and potential influences on cervical remodeling of minor ECM, and non-ECM, components. Ultimately, we envision a modeling tool that incorporates both imaging and biological biomarkers for a comprehensive picture of an individual's pregnancy, which will allow prediction of birth timing, and could even expose therapeutic targets for abnormal (preterm or postdates) timing.