Reduced uteroplacental blood flow (UPBF) and perfusion (UPP) commonly precede development of pregnancy complications including preeclampsia (PE) and fetal growth restriction (FGR), may be caused by suboptimal maternal vascular remodeling, and can lead to hypoxia. The initial trigger is unclear but may be associated with altered immune cell homing and/or activation at the maternal-fetal interface (MFI). Obesity is a common 'environmental insult' associated with FGR and PE, as well as an altered inflammation state. Our overall goal is to adopt innovative imaging modalities to measure human placental function in normal and obese pregnancy. Our interdisciplinary team of obstetric scientists, medical physicists/MRI radiologists, and perinatal biologists with placentl expertise, proposes a comprehensive set of 4 Specific Aims which will advance our ability to assess the placenta by developing real-time evaluation of function at a global scale (UPBF), a local scale (UPP, oxygenation), an immune cellular scale (inflammation visualization), and a molecular/ biochemical scale (multiplex assay of relevant analytes).
Specific Aim 1 : To develop a U/S, 2D, 4D flow MRI approach for the measurements of UPBF.
Specific Aim 2 : To develop perfusion and oxygen mapping by arterial spin labeling (ASL), intervoxel incoherent motion (IVIM) and blood oxygenation level-dependent (BOLD) MRI.
Specific Aim 3 A: To use a well characterized acute inflammation macaque model and an iron contrast agent to generate for the first time 3D high-resolution MRI maps of macrophages at the MFI in real time in vivo.
Specific Aim 3 B: To apply Fe-MRI to human pregnancy and determine if changes in immune cells are detectable before perfusion/oxygenation deficits; longitudinal blood/urine samples will be collected for cytokine and MMP analysis.
Specific Aim : 4: To comprehensively correlate data from all clinical imaging studies with pregnancy outcomes, and retrospectively analyze blood and urine collected from subjects for maternal serum growth factors, cytokines, and their regulated targets (MMPs). Overall, with these studies, we will have assessed whether the newly developed imaging technologies have improved predictive value over existing technologies and may better predict the initiation/activation of disease events observed by MRI that lead to adverse pregnancy outcomes. Progress in applying MRI modalities to the MFI and correlating with molecular analysis and clinical outcomes will lead to transformative ways to monitor the placenta during pregnancy, and provide an unparalleled window for timely initiation of future interventions to improve pregnancy outcomes in high-risk gestations.
Events at the interface of the fetal placenta and the wall of the maternal uterus during pregnancy is key to both the mother and future child's health. Anything that interferes with that process not only puts the mother and child at risk, but can also influenc the child throughout their adult lifespan. The events in early pregnancy that influence the function of the placenta are currently not understood because we have no way to examine the placenta inside the mother. We propose in this grant a collaboration between clinicians, medical imaging scientists, and placental biologists to provide new ways to directly visualize placental function in real time with the hope we will be able to identify problems that predict poor pregnancy outcomes, and in the future, intervene to protect the mother and child's health.
| Macdonald, Jacob A; Corrado, Philip A; Nguyen, Sydney M et al. (2018) Uteroplacental and Fetal 4D Flow MRI in the Pregnant Rhesus Macaque. J Magn Reson Imaging : |
