Novel biophysical and computational approaches towards understanding term and preterm labour.

The safe delivery of a healthy baby involves timely co-ordinated contraction of the muscle cells in
the uterus at the end of pregnancy. Unfortunately, in approximately 10% of pregnancies, the labour
contractions occur prematurely and result in early birth: 25 such babies die per week in the UK and
those that do survive have increased risk of severe physical or mental handicap. Our understanding
of how the human uterus contract is limited and therefore our ability to prevent or terminate
premature contractions is restricted.
Muscle contractions are controlled by electrical signals and calcium ions concentration within the
cells. The project will use advanced imaging methods to see, in uterine tissues, how the electrical
impulses and calcium concentration changes and how the effects of cell arrangement may influence
the flow of these activation signals between cells. We will look for differences of the signals that
underline normal labour and preterm labour. A detailed computer model based on these imaging
and structural data will be developed to assist our analysis in understanding how the labour
contractions start. A better understanding of how labour and premature labour state will help us to
design and test the safety of future drugs and treatment.

Preterm birth affects almost 60,000 pregnancies per year in the UK and is the most significant
contributor to neonatal death and chronic disability. In order to design better treatment for
premature labour, we need to develop quantitative models of the events controlling uterine smooth
muscle excitability at a cellular and tissue level. Uterine contractions during labour are coordinated
by spreading electrical activity and elevations of intracellular calcium in myometrial cells. However,
quantitative details of the genesis and propagation of uterine action potentials are scarce. The aim
of this project is to provide new experimental information and compute quantitative predictive
models of the mechanisms of excitation governing human uterine contractility. The transmembrane
voltage and intracellular calcium activities in myometrial tissues will be mapped macroscopically
(cm), using epi-fluorescence imaging methods, and microscopically (orders of im), using confocal
microscopy, each with high temporal resolution (msec). Morphological assessment of fibre
orientations from the same biopsies will also be undertaken by optical clearing or diffusion tensor
Magnetic Resonance Imaging. A principle aim is to use computational biology approaches to quantify
normal (spontaneous) and agonist-induced coupling, synchronisation and decoupling of voltage and
calcium changes in myometrial tissues of human and guinea pig (as an appropriate model of human
uterine function) and examine the influence of gestation, term labour and preterm labour. The
biophysical and morphological information will be utilised to construct, for the first time, a detailed
mathematical model of the spatiotemporal characteristics of excitation in the uterus that underpins
the contractile effort of labour; and the model will be validated with non-invasive multi-channel
electromyography recording of uterine electrical potentials. The model will be used in exploring
mechanistic details that initiate and underline normal and preterm labour, as well as to generate
testable hypotheses as to how the excitation activities changes by different interventions.
The medium-term benefits of this integrative computational biology approach will be to enable the in
silico construction of quantitative predictions that can be experimental tested to enable the
continued iterative advancement of the model and improved understanding of uterine physiology.
The longer-term benefits will be to apply such in silico predictions/hypotheses, and subsequent
experimental validations, to the assessment of new therapeutic agents for the treatment of
premature labour and/or dysfunctional labour at term, as well as to improve interpretation of human
uterine electrohysterography recording as a clinical prognostic tool, based upon putative modes of
action on uterine electrical activities.