Grant: Project Grant

The uterus is composed of the smooth muscle layers and epithelial tissue required for multiple reproductive functions in women. The activity of the smooth muscle component, the myometrium, generates the force needed to expel the fetus at birth. To initiate contractions, individual smooth muscle cells within the myometrium express a repertoire of genes in response to hormonal and inflammatory signals. In many patient cases, however, this multiple cell-coordinated contractile response occurs prior to term; women can consequently enter labour too early, which results in the delivery of underdeveloped infants at high risk of death or complications later in life. Recent research has identified genes up-regulated in term labour and preterm labour myometrium; however, the mechanisms that activate these genes remain unclear. To understand the basis of preterm labour and develop new preterm labour therapies, we need to find the molecular players involved in activating these genes in both term labour and preterm labour. In this project, we will find the genomic sequences and proteins that activate the expression of genes required for preterm labour in mouse and human myometrial tissue. To uncover the important regulatory sequences driving labour-specific gene activation, we will generate and compare the myometrial epigenetic profiles associated with gene regulatory sequences at different time points during pregnancy. We will next find the regulatory sequences activated in preterm labour using infection- and hormone-mediated mouse models as well as patient samples. Finally, we will find the critical regulatory sequence binding proteins needed to activate labour-specific genes in both labour types. Uncovering the suite of genomic regions and regulatory proteins that underlie the labour process will provide new targets for the development of therapeutic treatments for preterm labour, preventing complications that occur when babies are born preterm.