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: 10631080
• 负责人: Dinesh Manilal Shah
• 金额: $ 63.78万
• 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/10631080
• 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; Macrophage; Magnetic Resonance Imaging; Maps; 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; Spiral Artery of the Endometrium; Structure; Study Subject; 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; immunopathology; improved; in vivo; ischemic injury; 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）是对生物结构无创，实时可视化的强大工具，并采用精致方法，评估其相关功能以及生理和病理生理过程。在提供妊娠遍布胎盘健康的有趣机会的同时，由于胎儿安全问题，孕妇通常不会使用它。但是，这些方法的强大生物学潜力可以应用于实验动物模型，对于母体胎儿界面，从组织学，内分泌和免疫学的角度来看，非人类灵长类动物是与人类最引人注目的。我们已经优化了序列，并确定了在先前的研究中成像怀孕的猕猴子宫和孕妇界界面（MFI）的局限性，并验证了动态对比度增强（DCE），以评估胎盘间隔空间中的流量和灌注。在这笔赠款中，我们将应用我们既定的MRI方法在MFI处引起炎症或功能障碍的新型生理压力源，并确定它们作为NHP中的实验工具的可行性，用于在两个特定的目标中实时评估，体内，灌注，氧合，氧合和对胎儿生长限制（FGR）的进展。具体目的1。要利用巨噬细胞运输的生理刺激剂MCP1来定义MRI检测在母体 - 狂热界面处炎症的实用性，并具有开发FGR NHP模型的潜力。具体目的2。使用注射到MFI中的止血剂来产生血管病理学，触发炎症和绒毛缺血性损伤，以确定MRI的效用以鉴定与MFI处的血管病理相关的炎症，以及这种侮辱的潜力，有可能发展为FGR的NHP模型。在这些研究中，血氧水平取决于（BOLD）MRI将定义组织氧合和铁氧二醇DCE MRI MRI将评估吞噬细胞在MFI处保持对比剂的种群的无创变化，并将与最终的MACA相关。在UW-Madison，我们已经在怀孕的恒河猴中开发了铁氧基二醇成像，以评估胎盘灌注，并将这种方法转化为我们当前的人类胎盘项目U01 Grant，并通过批准的IRB人类学科研究。通过确认邻近的绒毛性低氧状状态和胎盘组织病理学和免疫病理学来验证胎盘灌注损伤的评估，将通过大大提高FGR诊断的准确性并增强我们对胎儿的识别能力极大的影响，从而促进临床护理，从而提高临床护理。