Understanding what triggers birth? New opportunities for prevention of early delivery
-
Associate Professor
Martha Lappas+61 3 8458 4370
Project Details
Within the discipline of reproductive biology, our understanding of one of the most fundamental biological processes is lacking – the cellular and molecular mechanisms that govern BIRTH. This lack of understanding limits our ability to reduce the incidence of labour complications. The incidence of labour complications including: preterm labour; cervical incompetence; and post-date pregnancies has not diminished in decades. The key to improving the management of human labour and delivery is an understanding of how the multiple processes that are requisite for a successful labour and delivery are coordinated to achieve a timely birth. Processes that include the formation of: contraction associated proteins [CAPs]; inflammatory mediators [eg cytokines]; uterotonic phospholipid metabolites [eg prostaglandins]; and the induction of extracellular matrix remodelling.
New approaches that identify and target the upstream regulators of multiple labour-associated processes are required if better management of labour is to be achieved. Over the last decade, my studies have identified a number of “master regulators” of the mechanisms that govern birth. My in vitro data has made it increasingly clear that a suite of regulators (e.g. nuclear factor-κB, NF-κB; peroxisome proliferator activated receptors, PPARs; activator protein, AP-1; sirtuin 1, SIRT1) coordinate the timely expression of the terminal effector pathways of labour and delivery. These master regulators may represent novel intervention points for developing therapeutics to reduce the incidence of preterm birth and related perinatal morbidity and mortality. In this project, we will thoroughly characterise their role in preterm birth and investigate their potential as a therapeutic intervention to prevent preterm labour using a mouse model of preterm birth.
Researchers
Funding
NHMRC
Norman Beischer Medical Research Foundation
Research Publications
Lim, R.; Lappas, M. A novel role for GSK3 in the regulation of the processes of human labour Reproduction (2015) 149(2):189-202
Lappas, M. KLF5 regulates infection- and inflammation-induced pro-labour mediators in human myometrium Reproduction (2015) 149 5 413-24
Lappas, M. Copper metabolism domain-containing 1 represses the mediators involved in the terminal effector pathways of human labour and delivery. Mol Hum Reprod. 2016 Apr;22(4):299-310.
Lim R, Tran HT, Liong S, Barker G, Lappas M. The Transcription Factor Interferon Regulatory Factor-1 (IRF1) Plays a Key Role in the Terminal Effector Pathways of Human Preterm Labor. Biol Reprod. 2016 Feb;94(2):32.
Lappas, M.; Permezel, M.; Georgiou, H. M.; Rice, G. E. Nuclear factor kappa B regulation of proinflammatory cytokines in human gestational tissues in vitro. Biol Reprod (2002) 67 2 668-73.
Lappas, M.; Mitton, A.; Lim, R.; Barker, G.; Riley, C.; Permezel, M. SIRT1 is a novel regulator of key pathways of human labor Biol Reprod (2011) 84 1 167-78.