Our long-term research goal is to improve pregnancy outcome and newborn health by supporting each fetus in attaining its innate growth potential. In this exploratory proposal, we deploy a novel research plan that centers on epigenomic signals that control placenta-maternal communication. We posit that microRNA and other small RNA signals have an extraordinary significance in regulation of placental and maternal gene expression and consequently, successful pregnancy. Unlike changes in DNA methylation, histone modifications or nucleosomal remodeling, miRNAs and other small RNAs directly modulate the expression of mRNAs and proteins. While prevalent in every tissue and capable of modulating diverse developmental, physiological and pathological processes, the function of most miRNA remains unknown. The placenta distinctively interfaces between the semi-allograft fetus and the maternal host. Importantly, the human placenta expresses unique miRNA species that are not normally present elsewhere. We have assembled a trans-disciplinary team that spans expertise in development, computational biology, and pathology, sharing the common goal of elucidating the role of microRNAs and small RNAs in the cross talk between the mother and the feto-placental unit. Having already defined differential microRNA expression and their unique function in primary human trophoblasts in normal and hypoxic conditions, we now seek to use next generation deep sequencing technology to comprehensively interrogate microRNA and small RNA species in the human maternal blood and the placenta, and deploy novel computational tools to analyze dynamic changes in microRNA and small RNA expression in normal pregnancies or pregnancies complicated by clinically relevant placental injury. We will specifically assess the nature of small RNAs assembled in vesicular nano-particles (exosomes), which may traffic small RNAs between the mother and the feto-placental unit. Information gleaned from our data may not only illuminate non-coding RNA pathways that influence human embryonic development, but may also suggest new, clinically-relevant signals, designed to inform the risk of placental injury and sub-standard pregnancy outcome.