Molecular and Cellular Controls of Placental Metabolism

胎盘代谢的分子和细胞控制

• 批准号: 8827833
• 负责人: Yoel Sadovsky
• 金额: $ 100.98万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827833
• 关键词: Adult; Biological Markers; Biology; Birth; Childhood; Clinical; Clinical Research; Communication; Data; Defect; Development; Discipline; Disease; Embryo; Epigenetic Process; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetus; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Genomics; Glycogen; Health; Hemorrhage; Hormones; Injury; Knowledge; Laboratories; Ligands; Lipids; Maintenance; Maternal Health; Metabolic; Metabolic Pathway; Metabolism; Molecular; Molecular Genetics; Morphology; Mus; Neonatal; Nutrient; Obesity; Organogenesis; Pathogenesis; Placenta; Placentation; Play; Positioning Attribute; Pregnancy; Premature Birth; Prevention; Process; Protein Family; Regulation; Research; Risk; Role; Stress; System; Technology; Therapeutic; Tissues; base; cofactor; fetal; high throughput analysis; imprint; innovation; novel; programs; stem; stillbirth; trophoblast

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.

描述（由申请人提供）：胎盘在胎儿生长和妊娠健康中起着至关重要的作用。在整个妊娠期和出生前，胎盘对胚胎器官形成、胎儿生长、免疫支持和维持健康的母胎交流是必不可少的，同时保护产妇健康。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，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，与胎盘功能障碍相关的胎盘应激激素和绒毛膜下出血也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，最近通过基因表达的高通量分析得到加强，定义了胎盘损伤，但未能阐明其对胎儿的代谢后果。因此，我们从组织形态学和分子构建块的静态数据推断并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手解开胎盘燃料储存的代谢、它们对胎儿的可用性以及滋养层储存失调的影响。 热量营养素对胎儿-胎盘发育的影响。从几个学科特定的角度来看，我们的团队精心制作了一个跨学科的倡议，该倡议集中在胎盘代谢损伤的创新分析上，这些损伤源于异常的分子，表观遗传（印记）和细胞影响，并干扰胎盘储存和热量营养素的利用。我们的计划集中在胎盘糖原和脂质库。我们试图理解（a）通过鉴定DNMTIO缺陷胎盘中的功能缺陷，印迹在小鼠胎盘代谢功能中的作用，（B）转录调节因子PPARY及其转录辅因子LCoR对胎盘糖原储备的转录和发育调节（配体依赖性辅阻遏物），和（c）胎盘损伤对脂滴代谢、Plin家族蛋白和滋养层脂毒性的影响。我们利用新的，快速发展的小鼠遗传和表观遗传技术的力量，以及高通量基因组学和脂质组学分析，以回答胎盘生物学中基于系统的基本问题，并提供有关分子代谢途径的新观点，这些分子代谢途径是临床难题的基础。我们的发现可能为疾病生物标志物，治疗和预防的临床研究铺平道路。