Molecular and Cellular Controls of Placental Metabolism

描述（申请人提供）：胎盘在胎儿生长和妊娠健康中起着至关重要的作用。在整个妊娠期和分娩期间，胎盘对于胚胎器官发生、胎儿生长、免疫支持和维持母胎健康交流是必不可少的，同时也保护了孕产妇的健康。胎盘处于支持胎儿发育的中心位置，是各种宫内损伤的目标，包括表观遗传、遗传、分子和获得性扰动，这些扰动影响常见的严重妊娠疾病，包括胎儿生长受限。此外，胎盘应激激素和绒毛膜下出血都与胎盘功能障碍有关，与早产的发病机制有关。胎盘功能障碍在发育中的胚胎上留下了印记，使其容易受到许多儿童和成人疾病的影响。已建立的表征胎盘功能障碍的组织形态学方法，最近通过高通量基因表达分析得到了加强，定义了胎盘损伤，但未能阐明其对胎儿的代谢后果。因此，我们从组织形态和分子构建块的静态数据推断和阐明胎盘代谢的动态过程的能力受到阻碍。这种知识差距与我们对胎盘储存和代谢燃料动员的理解有关，这对胎儿发育至关重要。认识到这些缺陷，我们的三个实验室联合起来揭示胎盘燃料储存的代谢，它们对胎儿的可用性，以及滋养细胞储存失调的影响

DESCRIPTION (provided by applicant): The placenta plays an essential role in fetal growth and pregnancy health. Throughout pregnancy and until birth, the placenta is obligatory for embryonic organogenesis, fetal growth, immunological support, and maintenance of healthy maternal-fetal communication, while preserving maternal health. Centrally positioned to support fetal development, the placenta is a target for diverse intrauterine injuries, spanning epigenetic, genetic, molecular, and acquired perturbations, which impact common, severe diseases of pregnancy, including fetal growth restriction. Moreover, placental stress hormones and sub-chorionic bleeding, both associated with placental dysfunction, are implicated in the pathogenesis of preterm birth. Placental dysfunction leaves its mark on the developing embryo, rendering it vulnerable to a host of childhood and adult diseases. Established histomorphological approaches to characterize placental dysfunction, recently fortified by high throughput analysis of gene expression, define placental injury yet fail to illuminate its metaboli consequences to the fetus. Hence, our ability to infer from static data on tissue morphology and molecular building blocks, and elucidate the dynamic process of placental metabolism, is hampered. This knowledge gap is pertinent to our understanding of placental storage and mobilization of metabolic fuels, which are critical for fetal development. Recognizing these deficiencies, our three laboratories have joined forces to unravel the metabolism of placental fuel stores, their availability to the fetus, and the impact of dysregulated trophoblast storage of caloric nutrients on feto-placental development. Drawing from several discipline-specific perspectives, our team crafted a transdisciplinary initiative that centers on innovative analyses of placental metabolic injury that stems from aberrant molecular, epigenetic (imprinting) and cellular influences, and perturbs placental storage and utilization of caloric nutrients. Our program centers on placental glycogen and lipid depots. We seek to understand (a) the role of imprinting in the metabolic function of the mouse placenta by identifying the functional defects in DNMTIo-deficient placentas, (b) the transcriptional and developmental regulation of placental glycogen stores by the transcriptional regulator PPARY and its transcription cofactor LCoR (Ligand-dependent CoRepressor), and (c) the impact of placental injury on lipid droplet metabolism, Plin family proteins, and trophoblast lipotoxicity. We harness the power of new, rapidly evolving mouse genetic and epigenetic technologies, as well as high throughput genomics and lipidomics analyses, to answer fundamental systems-based questions in placental biology, and offer a novel view on molecular metabolic pathways that underlie a clinical conundrum. Our findings may pave the way to clinical research into disease biomarkers, therapeutics and prevention.