A precise and well-orchestrated set of molecular and cellular signals governs the differentiation and function of the luman placenta. Surfacing the placental villi, the trophoblast bilayer of the human placenta is well positioned to execute a series of functions that are essential for placental metabolism, and consequently facilitate fetal development. Whereas recent studies illuminated spatial and temporal pathways that influence transcriptional regulation of trophoblast genes in mouse, sheep and human placentas, little is known about the integration of these signals into maintenance of trophoblast tiomeostasis and placental adaptation to injury. Practically unknown five years ago, microRNAs (miRNAs) are ubiquitously expressed in tissues of diverse organisms, from worms to humans. As a part of the endogenous RNA silencing machinery, these short RNA strands act in concert with the RNA interference silencing complex to degrade target transcripts and silence translation, and thereby regulate development and maintain homeostasis. Moreover, dysregulated miRNA expression has been implicated in human diseases. We and others have recently shown that both the mouse and human placentas express miRNAs, yet their pattern of expression and function are unknown. Considering the fundamental role of the placenta in development of the mammalian embryo, as well as the profound consequences of placental dysfunction, it is paramount to investigate the function of miRNAs in this organ. This exploratory translational research project, which bridges recently discovered miRNA pathways to human trophoblast biology and disease, matches the R21 funding objectives. In the proposed work we will test the hypothesis that discrete miRNA species are expressed in human trophoblasts and regulate normal placental function as well as adaptive response to hypoxic injury. Information gleaned from our studies will likely shed light on novel mechanisms that govern trophoblast adaptive response to injury, and uncover the role of endogenous RNAi in the differentiation and function of the human placenta. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD053878-02
Application #
7270100
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
2006-08-01
Project End
2007-11-07
Budget Start
2007-08-01
Budget End
2007-11-07
Support Year
2
Fiscal Year
2007
Total Cost
$27,761
Indirect Cost
Name
Washington University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Donker, R B; Mouillet, J F; Chu, T et al. (2012) The expression profile of C19MC microRNAs in primary human trophoblast cells and exosomes. Mol Hum Reprod 18:417-24
Rosario, F J; Sadovsky, Y; Jansson, T (2012) Gene targeting in primary human trophoblasts. Placenta 33:754-62
Mouillet, J-F; Chu, T; Hubel, C A et al. (2010) The levels of hypoxia-regulated microRNAs in plasma of pregnant women with fetal growth restriction. Placenta 31:781-4
Mouillet, Jean-Francois; Chu, Tianjiao; Nelson, D Michael et al. (2010) MiR-205 silences MED1 in hypoxic primary human trophoblasts. FASEB J 24:2030-9
Donker, Rogier B; Mouillet, Jean-Francois; Nelson, D Michael et al. (2007) The expression of Argonaute2 and related microRNA biogenesis proteins in normal and hypoxic trophoblasts. Mol Hum Reprod 13:273-9