Validation of the guinea-pig as an appropriate model for human labour: HDAC inhibitors as tocolytics for preterm labour.

Preterm labour (PTL) continues to be a major complication of pregnancy in the 21st Century for which there is no broadly effective therapeutic clinical strategy. Whilst most infants are delivered at the end of a full-term pregnancy, nearly 60,000 per year in the UK are born early because the mother goes into labour too soon. Prematurely born children may face a high risk of disability and life-long ill health. However, despite intensive research we remain unable to prevent PTL. One of the fundamental problems is our poor understanding of the co-ordinated contractions in the muscles of the uterus which lead to delivery and how to inhibit them with drugs. This failure is also linked to a lack of suitable animal models reflective of human labour in which we can develop new drug therapies for PTL. This Collaborative Project Grant brings together international experts with the common goal of addressing these issues. In particular, we will test our suggestion that the pregnant guinea pig serves as a useful model uterine contraction and human labour over that of currently favoured rodent models. We will do this by examining if new drugs that inhibit a class of molecules known as HDACs can actually reduce the incidence or severity of PTL in this guinea pig model. If so, they will offer new possibilities for the clinical treatment in humans of PTL.

Pre-term labour (PTL) remains one of the most pressing unresolved complications of pregnancy and is an important precedent of chronic disability and adult ill-health. In order to develop improved and successful clinical management strategies for PTL, there is a fundamental need to (i) increase our awareness of how uterine contractility is controlled during normal pregnancy and in cases of preterm labour and (ii) to rigorously test in an appropriate animal model the efficacy of new drugs as in vivo tocolytics (inhibitors of uterine contraction). It is to this end that our collaborative grouping has arisen. Each group brings to the collaboration unique expertise that results in a wide range of complementary skills and experimental approaches that would not be available outwith a collaborative effort. The applicants study the molecular and cellular remodelling mechanisms occurring in the uterus in preparation for the timely co-ordination of powerful contractions at term and how these may have been aberrantly regulated in the situation of preterm labour. Our breadth of research expertise covers molecular cell biology, tissue level physiology and in vivo animal physiology. In particular, our grouping seeks to use this Collaboration Grant to focus efforts on: (i) developing a non-primate animal model (guinea pig) of parturition and preterm labour that is more relevant to the human setting and (ii) in parallel to our MRC parent grant, test the efficacy of Histone Deacetylase (HDAC) inhibitors as tocolytics for preterm labour in vivo. We propose that the guinea pig, although recently utilised far less than mice, rats or sheep in the field of parturition and PTL, has the tremendous advantage of the regulation of parturition, notably the lack of a maternal serum progesterone withdrawal, being strikingly similar to the human. As such our collaborative group will experimentally validate the proposal that the guinea pig is an appropriate and pragmatic non-primate model of preterm labour with which to the explore the molecular mechanisms of uterine activation (the guinea pig genome is now sequenced) and also develop improved protocols for translating our biological findings to therapeutic developments of clinical significance. For this last, we will assess the ability of two mechanistically distinct HDAC inhibitors to forestall premature delivery in three paradigms of guinea pig preterm labour.