Magnetic resonance imaging of the antecedents of fetal growth restriction at the primate maternal-fetal interface

磁共振成像（MRI）是一种强大的工具，用于非侵入性，实时可视化生物结构，并采用精确的方法，评估其相关功能以及生理和病理生理过程。虽然提供了在整个妊娠期间探测胎盘健康的有趣机会，但由于胎儿安全问题，它并不经常用于孕妇。然而，这些方法的强大生物学潜力可以应用于实验动物模型，并且对于母体-胎儿界面，从组织学、内分泌和免疫学的角度来看，非人灵长类动物是与人类最引人注目的平行物。我们已经优化了序列，并确定了在以前的研究中对妊娠猕猴子宫和母胎界面（MFI）进行成像的局限性，并验证了动态对比增强（DCE）用于评估胎盘绒毛间隙中的血流和灌注。在这项研究中，我们将应用我们建立的MRI方法，在MFI产生炎症或功能障碍的新的生理应激源，并确定其作为实验工具的可行性，在NHP评估，在真实的时间在体内，灌注，氧合，并在两个特定的目的进展到胎儿生长受限（FGR）。具体目标1。利用巨噬细胞运输的生理刺激物MCP 1，确定MRI在检测母胎界面炎症中的实用性及其开发FGR NHP模型的潜力。具体目标2。使用注射到MFI中的止血剂来产生血管病理，触发炎症和绒毛缺血性损伤，以确定MRI在鉴别与MFI处的血管病理相关的炎症方面的效用，以及这种损伤开发FGR的NHP模型的潜力。在这些研究中，血氧水平依赖性（BOLD）MRI将定义组织氧合，ferumoxytol DCE MRI将评估MFI下保留造影剂的吞噬细胞群体的非侵入性变化，与绒毛间灌注、氧合、组织病理学以及细胞和分子免疫反应相关，我们预测这些反应最终将通过猕猴中FGR的发展表现出来。在UW-Madison，我们已经在妊娠恒河猴中开发了ferumoxytol成像，以评估胎盘灌注，并在我们目前的人类胎盘项目U 01资助中将这种方法转化为临床，并批准了IRB人类受试者研究。通过确认相邻绒毛缺氧状态和胎盘组织病理学和免疫病理学，用DCE评估胎盘灌注不足病变，将通过显著提高FGR诊断的准确性和增强我们识别具有显著低氧血症后果的最大风险的胎儿的能力来推进临床护理。

Magnetic Resonance Imaging (MRI) is a powerful tool for the noninvasive, real-time visualization of biological structures and with refined approaches, the assessment of their associated functions and physiological and pathophysiological processes. While providing intriguing opportunities to probe placenta health across gestation, it is not routinely used in pregnant women due to fetal safety concerns. However, the powerful biological potential of these approaches can be applied to experimental animal models, and for the maternal- fetal interface, the nonhuman primate is the most compelling parallel to the human from a histological, endocrine and immunological perspective. We have optimized the sequences and determined the limitations for imaging the pregnant macaque uterus and maternal-fetal interface (MFI) in previous studies, and validated dynamic contrast enhancement (DCE) for assessing flow and perfusion in the placental intervillous space. In this grant we will apply our established MRI approaches to novel physiological stressors generating inflammation or dysfunction at the MFI and determine their feasibility as experimental tools in NHPs for assessing, in real time in vivo, perfusion, oxygenation, and progression to fetal growth restriction (FGR) in two Specific Aims. Specific Aim 1. To utilize a physiological stimulator of macrophage trafficking, MCP1, to define the utility of MRI in detecting inflammation at the maternal-fetal interface and its potential to develop an NHP model of FGR. Specific Aim 2. To use a hemostatic agent injected into the MFI to create vascular pathology, triggering inflammation and villous ischemic injury to define the utility of MRI to identify inflammation associated with vascular pathology at the MFI, and the potential for this insult to develop an NHP model of FGR. In these studies blood oxygen level dependent (BOLD) MRI will define tissue oxygenation and ferumoxytol DCE MRI will assess noninvasively changes in the populations of phagocytic cells retaining contrast agent at the MFI, to be associated with intervillous perfusion, oxygenation, histopathology, and cellular and molecular immune responses that we predict will ultimately manifest by the development of FGR in the macaque. At UW-Madison we have developed ferumoxytol imaging in the pregnant rhesus monkey to evaluate placental perfusion and translated this approach to the clinic in our current Human Placenta Project U01 grant with an approved IRB Human Subject study. Assessment of placental hypoperfusion lesions with DCE validated by confirmation of an adjacent villous hypo-oxygenated state and placental histopathology and immunopathology, will advance clinical care by dramatically improving the accuracy of diagnosis of FGR and enhancing our ability to identify fetuses at greatest risk for consequences of significant hypoxemia.