Molecular and Cellular Controls of Placental Metabolism

胎盘代谢的分子和细胞控制

• 批准号: 8643807
• 负责人: Yoel Sadovsky
• 金额: $ 99.89万
• 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643807
• 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。在整个怀孕和出生之前，胎盘对胚胎器官发生，胎儿生长，免疫支持以及维持健康的母亲沟通的维护是必不可少的，同时保留了产妇的健康。胎盘以支持胎儿发育的中心位置，是跨越体内损伤的靶标，涵盖表观遗传，遗传，分子和获得的扰动，这会影响常见的，包括胎儿生长限制在内的常见，严重的妊娠疾病。此外，胎盘应激激素和亚修正理出血都与胎盘功能障碍有关，与早产的发病机理有关。胎盘功能障碍在发育中的胚胎上留下了痕迹，使其容易受到童年和成人疾病的影响。建立的组织形态方法是表征胎盘功能障碍的表征，最近通过对基因表达的高吞吐量分析所强化，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中推断出来，并阐明胎盘代谢的动态过程。这种知识差距与我们对胎盘储存和动员代谢燃料的理解有关，这对于胎儿发育至关重要。认识到这些缺陷，我们的三个实验室已经联手揭示了胎盘燃料商店的代谢，它们对胎儿的可用性以及失调的滋养细胞存储的影响 热量营养素在胎儿开发方面。从几个学科特定的角度来看，我们的团队制定了一项跨学科计划，该计划的重点是胎盘代谢损伤的创新分析，源于异常的分子，表观遗传（印迹）和细胞影响，并依赖胎盘储存和使用热量营养素。我们的程序集中于胎盘糖原和脂质库。我们试图通过识别DNMTIO缺陷胎盘中的功能缺陷来了解（a）烙印在小鼠胎盘的代谢功能中的作用，（b）通过转录调节剂的转录调节器和转录cof cof cof cof-lcor（ligand core）的转录和发展依赖性依赖性的胎盘基因储存的转录和发育调节，并依赖于ligand依赖性依赖性（依赖Ligant）。液滴代谢，PLIN家族蛋白和滋养细胞脂肪毒性。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，以及高吞吐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，并提供对分子代谢途径的新颖观点，这些途径构成了临床结合的基础。我们的发现可能为疾病生物标志物，治疗剂和预防的临床研究铺平道路。