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

理解分娩的多模态、多尺度方法

• 批准号: 10200861
• 负责人: Helen Feltovich
• 金额: $ 67.45万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200861
• 关键词: Acceleration; Address; Adhesions; Affect; Anatomy; Biochemical; Biological; Biological Markers; Biomechanics; Birth; Birth Rate; Blood; Blood Vessels; Cervical; Cervix Uteri; Collagen; Complex; Conceptions; Dimensions; Drug or chemical Tissue Distribution; Elements; Environment; Extracellular Matrix; Fetal Membranes; Finite Element Analysis; First Pregnancy Trimester; Future; Geometry; Goals; Human; Image; Individual; Intervention; Knowledge; Link; Macaca; Macaca mulatta; Measurement; Measures; Membrane; Minor; Modeling; Modulus; Molecular; Patients; Permeability; Play; Pregnancy; Pregnant Women; Premature Birth; Process; Property; Rhesus; Role; Sampling; Second Pregnancy Trimester; Societies; Stretching; Structural Models; Structure-Activity Relationship; Techniques; Technology; Third Pregnancy Trimester; Tissues; Ultrasonography; Uterus; Work; base; biomechanical model; cervical remodeling; design; exhaust; flexibility; imaging biomarker; in vivo; informant; insight; mechanical load; mechanical properties; multimodality; quantitative ultrasound; soft tissue; statistics; success; therapeutic target; tissue stress; tool; viscoelasticity

Project Summary The U.S. preterm birth rate is increasing 1 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.

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筛查并提供 即使采取适当的干预措施，95%的肺结核仍会发生，2这两个因素都表明我们已经用尽了 所有目前可用的选择，并反映了我们的分子机制的理解不足，这 这是一个复杂而普遍的问题，影响着世界上的每一个社会。我们实验室的最新发现挑战了 妊娠期宫颈重塑的现有范例。他们认为，也许在分娩前成熟是 不是简单的加速或增强从受孕后逐渐发生的软化 通过交付，而是由完全不同的机制驱动，可能是由较小的ECM组件和/或 非ECM组件，其中一些可能仍然无法识别。我们开始怀疑 在ECM中，尽管子宫颈持续软化和丧失，但达到一个点后，它不再重新排列 的强度，和非ECM成分（如血管）发挥重要作用。这些发现暗示， 一个令人信服的替代范式宫颈重塑，但更重要的是，他们揭示了一个很大的知识差距 我们对分娩的理解。我们的目标是解决这一差距，并探索这一潜在的新的 范例，通过构建描绘结构-功能关系的患者特异性生物力学模型 子宫颈和其他支持胎儿的组织（膜，子宫），基于特定的测量， 宫颈微结构和母体解剖结构。我们还将探讨潜在的贡献 宫颈重塑的次要细胞外基质（ECM）和非ECM信息。为此，我们将利用我们的 纵向测量体内组织显微结构特性和母体解剖学的恒河猴模型 在整个怀孕期间使用超声，制定和验证超声参数之间的关系 和组织材料特性的子宫颈在离体妊娠时间的样品，探索之间的关系， 组织生化成分和材料特性的子宫颈，子宫，和胎膜使用前 体内样本，并计算每个组织应力和拉伸的精确大小和区域分布 猕猴使用有限元分析直接告知她的个人微观结构组织和解剖 特性.基本模型将具有足够的灵活性，以最终容纳其他潜在的贡献者 宫颈重塑，如轻微ECM因素，或非ECM因素。为此，我们将在 我们目前的R 01的成功，通过扩展我们的恒河猴模型，深入探讨宫颈癌之间的关系， 显微结构和母体解剖学，并寻找宫颈生物力学特性之间的相关性 以及对微小ECM和非ECM成分的宫颈重塑的潜在影响。最终，我们设想 一种建模工具，它结合了成像和生物标志物，用于全面了解 这将允许预测出生时间，甚至可能暴露治疗目标， 异常（早产或过期）时间。