Mediated Signalling Mechanisms

Supervisors: Dr Mark Read, Dr Giavanna Angeli

Project Summary

Premature birth occurs in 5-10% of births and is associated with 70-80% of neonatal mortality. Arguably a greater problem exists among the survivors of preterm births who are at high risk for intellectual handicap. Approximately 50% of cases of cerebral palsy are related to preterm birth. Unfortunately the rate of preterm birth has not changed significantly in the last 30 years and trends indicate that it may be increasing. Our inability to diagnose and treat patients with pre-term labour is largely due to our ignorance of the fundamental mechanisms that control the process of normal human labour.

Corticotropin-releasing hormone (CRH) is a 41 amino acid polypeptide that exerts a wide spectrum of effects in the CNS and in peripheral tissues. During pregnancy, the placenta and other intrauterine tissues produce and secrete immunoreactive CRH. CRH is secreted into the mother's circulation in large amounts during the third trimester of human pregnancy and may play an important role in the onset of labour. CRH exerts a number of functions within the intrauterine environment including stimulation of prostaglandin production in the fetal membranes and maintenance of the placental blood flow.

Placentally derived CRH plays a major role in the mechanisms controlling human pregnancy and parturition. It has been suggested that there is a CRH placental clock that is active from the early stages of pregnancy and determines the length of gestation and the timing of parturition. Generally CRH receptors are coupled to cAMP, such as occurs in the hypothalamus and myometrium. Fetal and placental membranes express high levels of CRH receptors, specifically CRH-R1?, along with other splice variants CRH-R1c and CRH-R1d. However, CRH receptors in human placental and fetal membranes do not couple to cAMP and appear to be preferentially linked to mechanisms leading to an increase in intracellular inositol phosphate levels. These mechanisms are poorly understood and their importance in pregnancy and labour needs to be determined. This project involves an examination of CRH mediated signal transduction pathway in JEG-3 choriocarcinoma cells, a cell line derived from human fetal membranes. Specifically the cell signalling pathways activated by CRH via CRH-1a receptors will be determined. The methodologies employed in this study will include recombinant gene technology, cellular biochemistry and pharmacological approaches.