An exciting new field in medicine and science is the discovery of microRNAs. MicroRNAs (miRNAs) are small highly conserved single-stranded non-coding RNA molecules that play a critical role in post transcriptional gene regulation. Emerging evidence, in many different biological arenas, has identified miRNAs as critical players in diseases states. MicroRNA 210 (miR-210) has emerged as a unique hypoxia-induced miRNA that is induced in many cell types. Whether miR-210 expression serves to augment or protect the pathologic response to hypoxia appears to be a cell, tissue and disease specific event. The role of miR-210 in trophoblast and placental function remains to be discovered and is the focus of this proposal. The novel hypothesis for this R21 is that miR-210 plays a critical role in trophoblast function early in pregnancy and aberrant expression of miR-210 results in placental dysfunction. We hypothesize that miR-210 is an important mediator of adverse pregnancy outcomes (APO)-which originate from placental dysfunction-such as preeclampsia, intrauterine growth restriction and fetal demise. In normal pregnancy, the placenta develops in relatively hypoxic conditions. We propose that, in some women, this period of hypoxia is more severe and/or prolonged;in turn, this hypoxia leads to aberrations in trophoblast invasion and function resulting in placental dysfunction with the eventual development of APOs. Our preliminary data support our hypothesis that miR-210 is a critical mediator of placental dysfunction. Using primary extravillous trophoblasts (EVTs), we have demonstrated the following: 1) miR-210 is significantly increased in EVTs exposed to hypoxia;2) over-expression of miR-210 in EVTs results in significantly impaired trophoblast invasion;and 3) blocking of endogenous miR-210 increases trophoblast invasion. These data support an essential role of miR-210 in regulation of trophoblast invasion and suggest that increased expression of miR-210 promotes a pathological state. Furthermore, using biospecimens from existing clinical trials, we have demonstrated that miR-210 is increased in maternal blood at the time of diagnosis of an APO compared to women without these adverse outcomes. Importantly, we have also demonstrated that miR-210 levels are also increased in maternal blood months prior to the clinical onset of such APOs. These data suggest that miR-210 may not just a potential biomarker of APOs but also may be mechanistically involved in the development of the placental dysfunction. To further explore the role of miR- 210 in trophoblast function, we have created a mouse model of local intrauterine hypoxia to explore how a more prolonged period of intrauterine hypoxia alters placental function. In this model, there is fetal loss and a molecular phenotype consistent with persistent hypoxic pathways only in the placenta. While other rodent models used to study hypoxia-induced trophoblast dysfunction utilize systemic hypoxia, our model creates a hypoxic environment only at the level of the feto-placental unit. Using both in vitro (EVTs) and in vivo models, we will explore if miR-210 is an important and novel mediator of placental dysfunction.
MicroRNAs have been revealed as important mediators of pathogenic states. MicroRNA-210 has been discovered as an essential mediator to hypoxia. Based on strong preliminary data, this proposal will address if microRNA-210 is a novel and critical mediator of trophoblast function.
