The placenta mediates the transfer of respiratory gases, water, ions, and nutrients between mother and fetus, provides an immunological interface for fetal allograft survival, and secretes a vast array of signaling molecules to optimiz pregnancy physiology. Placental dysfunction evolves when one or more of these processes are dysregulated. The maladapted placenta predisposes to clinical syndromes characterized by sub-optimal fetal growth, known as intra-uterine growth restriction (IUGR), or hypertensive disorders such as preeclampsia (PE), which jeopardize both the fetus and mother. Current methods for assessing placental transport and secretion in vivo are limited, and assessment of oxygen status in the human fetus currently depends on indirect measures, such as monitoring heart rate and biophysical parameters that are affected by hypoxia. The overall goal of this grant is to develop and validate robust, non-invasive imaging technologies for placental function assessment that will readily translate to human studies. We propose to apply state-of-the-art, non-invasive imaging modalities to compare and contrast transport functions, metabolism, and oxygen concentrations during placental development of control C57BL/6 pregnant mice with three mouse models of pregnancy pathology, which simulate hypoxia, IUGR, or PE. We will extend our pre-clinical studies for the direct measurement of placental oxygenation in the mouse models and pursue proof-of-principle studies to determine oxygen transport and hemoglobin saturation in the human placenta in situ in control, uncomplicated pregnancies and pregnancies with IUGR, between 32-37 weeks' gestation. Finally, we propose to use phage display in preclinical mouse placental models, with validation in ex vivo human term placentas from normal, IUGR and PE pregnancies, with the goal of discovery novel peptide imaging targets that may serve as markers of pregnancy disorders or that may offer a means for targeted drug delivery to the fetoplacental unit. We will accomplish our goal of imaging placental function and development by developing and validating magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) methods to probe mouse placental function, transport, and metabolism. Experiments in the pre-clinical models will include mapping of perfusion, oxygen saturation and transfer, and placental fluid dynamics by MRI, and measurement of fetoplacental nutrient transport and metabolic function, using hyperpolarized 13C MRS and PET. A proof-of-principle study in normal and IUGR pregnancies will assess the clinical translation of the oxygen saturation/transfer method for the direct measurement of oxygen content in maternal and fetal blood within the human placenta. The success of this proposal will yield new, practical, non- invasive approaches for determining placental function and metabolism.
This application proposes development of quantitative imaging markers to characterize placental function, transport, and metabolism, critical determinants of placental performance heretofore not accessible by noninvasive means. Upon translation to the clinic, these methods will have a major positive impact on the assessment and management of high-risk pregnancies.
|Oren, Roni; Fellus-Alyagor, Liat; Addadi, Yoseph et al. (2018) Whole Organ Blood and Lymphatic Vessels Imaging (WOBLI). Sci Rep 8:1412|
|Meinerz, Kelsey; Beeman, Scott C; Duan, Chong et al. (2018) Bayesian Modeling of NMR Data: Quantifying Longitudinal Relaxation in Vivo, and in Vitro with a Tissue-Water-Relaxation Mimic (Crosslinked Bovine Serum Albumin). Appl Magn Reson 49:3-24|
|Markovic, Stefan; Fages, Anne; Roussel, Tangi et al. (2018) Placental physiology monitored by hyperpolarized dynamic 13C magnetic resonance. Proc Natl Acad Sci U S A 115:E2429-E2436|
|Avni, Reut; Golani, Ofra; Akselrod-Ballin, Ayelet et al. (2016) MR Imaging-derived Oxygen-Hemoglobin Dissociation Curves and Fetal-Placental Oxygen-Hemoglobin Affinities. Radiology 280:68-77|