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

磁共振成像(MRI)是非侵入性、实时可视化生物结构的有力工具，具有精细的方法，可以评估它们的相关功能以及生理和病理生理过程。虽然它提供了有趣的机会来探索怀孕期间的胎盘健康，但出于对胎儿安全的考虑，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，对于母胎界面，从组织学、内分泌和免疫学角度来看，非人类灵长类动物与人类最相似。在以前的研究中，我们已经优化了序列并确定了妊娠猕猴子宫和母胎界面(MFI)的成像限制，并验证了动态对比增强(DCE)技术用于评估胎盘绒毛间间隙的血流和血流灌注。在这笔赠款中，我们将把我们已建立的MRI方法应用于在MFI产生炎症或功能障碍的新的生理应激源，并确定它们作为NHP的实验工具的可行性，以在体内实时评估灌流、氧合和进展为胎儿生长受限(FGR)的两个特定目标。具体目的1.利用巨噬细胞运输的生理刺激物MCP1，确定MRI在检测母胎界面炎症方面的作用及其建立FGR的NHP模型的可能性。具体目的2.使用注射到MFI中的止血剂造成血管病理，引发炎症和绒毛缺血性损伤，以确定MRI在识别与MFI血管病理相关的炎症方面的作用，以及这种损害发展成FGR的NHP模型的可能性。在这些研究中，血氧水平依赖(BOLD)MRI将定义组织氧合作用，阿魏酸甲酯DCE MRI将评估保留MFI造影剂的吞噬细胞种群的非侵入性变化，以与绒毛间灌流、氧合、组织病理学以及细胞和分子免疫反应相关，我们预测这些变化最终将通过猕猴FGR的发展而表现出来。在威斯康星大学麦迪逊分校，我们已经在怀孕的恒河猴身上开发了阿魏酸成像，以评估胎盘的血流灌注，并将这种方法转化到我们目前的人类胎盘项目U01拨款中，并批准了IRB人类受试者研究。DCE对胎盘低灌注病变的评估，通过确认邻近绒毛低氧状态以及胎盘组织病理学和免疫病理学，将极大地提高FGR诊断的准确性，并增强我们识别显著低氧血症后果的最高风险胎儿的能力，从而促进临床护理。

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.