Molecular and Cellular Controls of Placental Metabolism

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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.