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

灵长类母胎界面胎儿生长受限前因的磁共振成像

• 批准号: 10404011
• 负责人: THADDEUS G GOLOS
• 金额: $ 64.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-12 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404011
• 关键词: 4D MRI; Address; Anatomy; Animals; Biological; Biophysics; Blood Vessels; Blood flow; Body Regions; CCL2 gene; Cardiovascular system; Clinic; Contrast Media; Endocrine; Experimental Animal Model; FDA approved; Fetal Development; Fetal Growth Retardation; Fetal safety; Fetus; Fibrin Tissue Adhesive; Functional disorder; Goals; Grant; Health; Hemostatic Agents; Histologic; Histopathology; Human; Hypoxemia; Hypoxia; Image; Immune response; Immunologics; Infiltration; Inflammation; Institutional Review Boards; Intervention; Lesion; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Maternal-Fetal Exchange; Maternal-fetal medicine; Measures; Methodology; Methods; Modeling; Molecular; Mothers; Motion; Organ; Pathologic; Pathology; Perfusion; Phagocytes; Physiological; Physiology; Placenta; Population; Positioning Attribute; Pregnancy; Pregnant Women; Primates; Process; Prospective Studies; Reproducibility; Risk; Scanning; Second Pregnancy Trimester; Sequence Analysis; Spiral Artery of the Endometrium; Structure; Study Subject; Study of magnetics; Third Pregnancy Trimester; Time; Tissues; Translating; Uterus; Validation; Vascular blood supply; Villous; Visualization; Work; adverse pregnancy outcome; arterial spin labeling; blood oxygen level dependent; clinical application; clinical care; contrast enhanced; diagnostic accuracy; ferumoxytol; fetal; human subject; hypoperfusion; imaging approach; immunopathology; improved; in vivo; ischemic injury; macrophage; model development; nonhuman primate; novel; novel strategies; physiologic stressor; predicting response; pregnant; prognostic value; tissue oxygenation; tool; trafficking; vascular bed

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.

磁共振成像 (MRI) 是一种强大的工具，可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以及生理和病理生理过程。虽然它提供了探索整个妊娠期胎盘健康状况的有趣机会，但出于胎儿安全的考虑，它并不常规用于孕妇。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引人注目。我们在之前的研究中优化了序列并确定了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隙中的血流和灌注。在这笔资助中，我们将把我们既定的 MRI 方法应用于在 MFI 处产生炎症或功能障碍的新型生理应激源，并确定它们作为 NHP 实验工具的可行性，用于在两个特定目标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 1. 利用巨噬细胞运输的生理刺激剂 MCP1 来确定 MRI 在检测母胎界面炎症方面的效用及其开发 FGR 的 NHP 模型的潜力。具体目标 2. 使用注射到 MFI 中的止血剂来创建血管病理学，引发炎症和绒毛缺血性损伤，以确定 MRI 识别与 MFI 血管病理学相关的炎症的效用，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，而ferumoxytol DCE MRI将无创地评估在MFI保留造影剂的吞噬细胞群体的变化，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相关，我们预测这些反应最终将通过猕猴中FGR的发展而显现出来。在威斯康星大学麦迪逊分校，我们开发了怀孕恒河猴的 ferumoxytol 成像技术，以评估胎盘灌注，并将这种方法转化为临床，并通过一项已批准的 IRB 人类受试者研究，纳入我们当前的人类胎盘项目 U01 资助中。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验证，用 DCE 评估胎盘低灌注病变，将显着提高 FGR 诊断的准确性，并增强我们识别处于严重低氧血症后果最大风险的胎儿的能力，从而推进临床护理。