Declining Prostaglandin Metabolising Activity
Supervisor: Associate Professor Tamas Zakar
Prostaglandin dehydrogenase is the key enzyme in the prostaglandin degradation pathway. Its principal function is to convert bioactive prostaglandins to inactive metabolites. In human pregnancy prostaglandin dehydrogenase restricts the passage of active prostaglandins from the prostaglandin rich fetal tissues to the uterine muscle. This is critical for the maintenance of pregnancy, because prostaglandins are potent stimulants of uterine contractions.
In recent studies, we have shown that post-transcriptional mechanisms control dehydrogenase levels in uterine tissues at the time of labour onset. These studies also showed that a premature decline in the activity may lead to the onset of preterm labour. This project will explore the role of post-transcriptional control of prostaglandin dehydrogenase expression in the initiation of premature labour. The first approach will be to determine whether prostaglandin dehydrogenase mRNA levels are regulated by the rate of mRNA degradation or by the differential processing of the primary transcript into functional and non-functional mRNA splice variants. To achieve this will require the establishment of a real time RT-PCR procedure that will measure mRNA degradation intermediates in uterine tissue. Tissue samples obtained following preterm labour will be analysed to provide information on the method of regulation in vivo. In the second, in vitro approach, intracellular signalling pathways will be activated in short-term incubations of the same tissue with appropriate agonists, and the effect on dehydrogenase mRNA degradation and transcript processing will be determined. These studies will indicate if inappropriate changes in regulatory processes lead to a premature decline in prostaglandin degrading activity and contribute to the causation of preterm birth.
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