INTEGRATED PLACENTAL IMAGING: NOVEL METHODS FOR PROBING FUNCTION AND METABOLISM

集成胎盘成像：探测功能和代谢的新方法

• 批准号: 9284282
• 负责人: Joel Richard Garbow
• 金额: $ 66.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284282
• 关键词: 37 weeks gestation; Affect; Allografting; Binding; Binding Sites; Biological Markers; Blood Circulation; Blood Vessels; Child; Clinic; Clinical; Data; Derivation procedure; Detection; Development; Diffuse; Diffusion; Disease; Drug Delivery Systems; Drug Targeting; Early Diagnosis; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Tissues; Fetus; Functional disorder; Goals; Grant; Hemoglobin; High-Risk Pregnancy; Homeostasis; Hormones; Human; Hypoxia; Image; Imaging Device; Imaging technology; Immune Tolerance; Immunologics; In Situ; Interleukin-10; Ions; Lead; Liquid substance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maps; Maternal-Fetal Exchange; Measurement; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular; Molecular Target; Monitor; Morphology; Mothers; Multimodal Imaging; Mus; Nutrient; Outcome; Oxygen; Pathologic; Pathology; Peptides; Performance; Perfusion; Phage Display; Physiological; Physiology; Placenta; Placental Insufficiency; Placentation; Play; Positron-Emission Tomography; Postpartum Period; Pre-Clinical Model; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnant Women; Process; Production; Pump; Rattus; Reagent; Signaling Molecule; Source; Syndrome; Technology; Time; Tracer; Translating; Translations; Urea; Validation; Water; base; biophysical properties; clinical translation; experimental study; fetal; fetal blood; heart rate monitor; hemodynamics; image guided intervention; imaging biomarker; imaging modality; improved outcome; in vivo; in vivo magnetic resonance spectroscopy; insight; magnetic resonance imaging biomarker; minimally invasive; molecular marker; mouse model; non-invasive imaging; novel; oxygen transport; postnatal; pre-clinical; preclinical study; pregnancy disorder; pregnant; public health relevance; quantitative imaging; respiratory gas; spectroscopic imaging; success; targeted imaging

 DESCRIPTION (provided by applicant): 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.

 描述（由申请人提供）：胎盘介导母亲和胎儿之间呼吸气体、水、离子和营养物质的转移，为胎儿同种异体移植物存活提供免疫界面，并分泌大量信号分子以优化妊娠生理学。当这些过程中的一个或多个失调时，胎盘功能障碍就会发生。不适应的胎盘易患以次优胎儿生长为特征的临床综合征，称为宫内生长受限（IUGR），或高血压疾病，如先兆子痫（PE），其危及胎儿和母亲。目前用于评估体内胎盘转运和分泌的方法是有限的，并且目前对人类胎儿中的氧状态的评估依赖于间接测量，例如监测受缺氧影响的心率和生物物理参数。这项资助的总体目标是开发和验证用于胎盘功能评估的强大的非侵入性成像技术，这些技术将很容易转化为人类研究。我们建议应用最先进的非侵入性成像方式来比较和对比对照C57 BL/6妊娠小鼠与三种妊娠病理学小鼠模型（模拟缺氧、IUGR或PE）胎盘发育过程中的运输功能、代谢和氧浓度。我们将扩展我们的临床前研究，在小鼠模型中直接测量胎盘氧合，并进行原理验证研究，以确定在对照、无并发症妊娠和IUGR妊娠（妊娠32-37周）中原位人胎盘中的氧转运和血红蛋白饱和度。最后，我们建议在临床前小鼠胎盘模型中使用噬菌体展示，并在正常、IUGR和PE妊娠的离体人类足月胎盘中进行验证，目的是发现新的肽成像靶点，这些靶点可作为妊娠障碍的标志物，或可提供靶向药物递送至胎儿胎盘单位的手段。我们将通过开发和验证磁共振成像（MRI）、磁共振波谱（MRS）和正电子发射断层扫描（PET）方法来探测小鼠胎盘功能、运输和代谢，从而实现胎盘功能和发育成像的目标。临床前模型中的实验将包括通过MRI绘制灌注、氧饱和度和转移以及胎盘流体动力学，以及使用超极化13 C MRS和PET测量胎儿胎盘营养转运和代谢功能。在正常和IUGR妊娠中进行的原理验证研究将评估血氧饱和度/转移方法的临床转化，以直接测量人胎盘内母体和胎儿血液中的氧含量。这项建议的成功将产生新的，实用的，非侵入性的方法来确定胎盘功能和代谢。