Molecular and Cellular Controls of Placental Metabolism

描述(由申请人提供)：胎盘在胎儿生长和妊娠健康中起着重要的作用。在整个怀孕期间和出生前，胎盘对胚胎器官发生、胎儿生长、免疫支持和维持健康的母胎沟通是必不可少的，同时保持产妇的健康。胎盘位于支持胎儿发育的中心位置，是各种宫内损伤的目标，涉及表观遗传学、遗传学、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。胎盘功能障碍会在发育中的胚胎上留下印记，使其容易受到一系列儿童和成人疾病的影响。已建立的描述胎盘功能障碍的组织形态方法，最近通过高通量的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件的静态数据推断胎盘新陈代谢的动态过程的能力受到了阻碍。这一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。认识到这些不足，我们的三个实验室联合起来，解开胎盘燃料储存的新陈代谢，它们对胎儿的可用性，以及滋养层细胞储存失调的影响。 热量营养对胎儿胎盘发育的影响。我们的团队从几个特定学科的角度出发，制定了一个跨学科的倡议，集中于对胎盘代谢损伤的创新分析，这种损伤源于异常的分子、表观遗传(印迹)和细胞影响，并扰乱了胎盘热量营养的储存和利用。我们的计划集中在胎盘糖原和脂类储备上。我们试图通过识别DNMTIo缺陷胎盘的功能缺陷来了解(A)印记在小鼠胎盘代谢功能中的作用，(B)转录调控因子PPARy及其转录辅因子LCOR(配体依赖的辅助抑制物)对胎盘糖原储存的转录和发育调节，以及(C)胎盘损伤对脂滴代谢、plin家族蛋白和滋养层脂肪毒性的影响。我们利用新的、快速发展的小鼠遗传和表观遗传技术以及高通量基因组学和脂质组学分析的力量，回答胎盘生物学中基于系统的基本问题，并对构成临床难题的分子代谢途径提供新的观点。我们的发现可能为疾病生物标志物的临床研究、治疗和预防铺平道路。

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.