Project 453063

There is currently no effective therapy to prevent the birth of the 13 million babies born preterm (PTB) each year. Importantly, we have shown that labour is preceded by an influx of maternal white blood cells (leukocytes) into the uterus, however, their role in the initiation of labour remains to be determined. We have identified inflammatory proteins (called chemotactic cytokines) that activate these leukocytes and cause them to target the myometrium. These cytokines are made by myometrial cells due to stretch of the uterine wall by the growing fetus or as a result of uterine infection. Normally, their synthesis is blocked by progesterone, which is elevated in the blood of pregnant women. However, during labour progesterone is destroyed inside uterine myocytes by an enzyme, 20alpha-HSD (HSD). Based on our preliminary data, we hypothesize that leukocytes directly interact with uterine myocytes and cause inactivation of progesterone through induction of HSD, leading to increased expression of myometrial genes required for labour. Thus, leukocyte-myocyte interaction represents a novel target for PTB therapeutics. In this project we will, 1) Use transcriptomics and imaging to define functional interactions between tissue macrophage and myocytes with the initiation of term/preterm labour. 2) Determine mechanisms by which this cellular interaction leads to PRA dominance, catabolism of P4 and the downstream increases in labour gene expression and myocyte contractility. 3) We anticipate we will identify novel targets for therapeutic intervention, including inhibition of a) macrophage activation/polarization, b) mac-myo cross-talk, c) ROS production, and d) broad-spectrum chemokine secretion, which will be explored through in vitro mechanistic studies. The most effective strategy will then be applied in-vivo, using targeted drug delivery in mouse models of preterm labour, as a pipeline to optimize novel therapeutic approaches for effective PTB prevention.