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，可以对生物结构进行无创、实时可视化，并通过精细的方法评估其相关功能、生理和病理生理过程。虽然提供了有趣的机会来探测整个妊娠期的胎盘健康，但由于胎儿安全问题，它并没有常规用于孕妇。然而，这些方法强大的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，内分泌和免疫学的角度来看，非人灵长类动物与人类最相似。我们优化了序列，确定了以往研究中对怀孕猕猴子宫和母胎界面（MFI）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间隙的血流和灌注。在这项资助中，我们将运用我们已建立的MRI方法来检测在MFI产生炎症或功能障碍的新型生理应激源，并确定其作为NHPs实验工具的可行性，用于在两个特定目的中实时评估体内灌注、氧合和胎儿生长受限（FGR）的进展。具体目标利用巨噬细胞运输的生理刺激因子MCP1，确定MRI在检测母胎界面炎症中的效用及其开发FGR NHP模型的潜力。具体目标2。将止血剂注射到MFI，造成血管病理，引发炎症和绒毛缺血性损伤，以确定MRI在MFI识别与血管病理相关的炎症的效用，以及这种损伤发展FGR的NHP模型的潜力。在这些研究中，血氧水平依赖（BOLD） MRI将定义组织氧合，阿威木酚DCE MRI将评估在MFI保留造影剂的吞噬细胞种群的无创变化，这些变化与绒毛间灌注、氧合、组织病理学以及细胞和分子免疫反应有关，我们预测这些变化最终将在猕猴FGR的发展中体现出来。在威斯康星大学麦迪逊分校，我们已经在怀孕的猕猴身上开发了阿魏糖醇成像技术来评估胎盘灌注，并将这种方法应用于我们目前的人类胎盘项目U01的临床研究，并获得了IRB批准的人类受试者研究。通过确认相邻绒毛缺氧状态以及胎盘组织病理学和免疫病理学验证DCE对胎盘灌注不足病变的评估，将通过显着提高FGR诊断的准确性和增强我们识别显著低氧血症后果风险最大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.