Rises in intracellular calcium are essential for contraction in myometrial smooth muscle. Calcium is not only an important second messenger for the generation of force via myosin light chain kinase, but also depolarizes the plasma membrane allowing for activation of other voltage dependent ion channels. This voltage dependent control of excitability is modulated in a gestation dependent manner in all mammalian species such that as gestation progresses the myometrium becomes increasingly excitable. These biophysical changes are mediated by alterations in ion channels, pumps, agonist receptors and the sub cellular architecture of heterogeneous cell types within the uterus. In order to consider the process of activation of the uterus in its entirety there is a requirement for a combination of molecular, biophysical, and modelling techniques.
Modelling the uterus:
We are currently developing a computational model of the human and rodent uterus. The model works on several levels, from classical Hodgkin-Huxley type modelling of time dependent active conductances in a single cell, through to coupled models of heterogeneous networks. We have assembled complete models of all active conductances in single cells for the purposes of drug discovery and investigating higher order phenomena such as functional redundancy. We have also assembled basic models of spatio-temporal patterns of excitability mapped to the full 3D geometry of the pregnant human and rat uteri. Our end goal is to have a computer based simulation of the pregnant human uterus to test quantitatively scientific ideas of cellular function; to model the effects of mutations in key genes; and to simulate complex phenomena in order to improve clinical treatments and diagnosis.
We have active ongoing research programmes with Ferring pharmaceuticals, GlaxoSmithKline and formerly with Medical Research Council Technologies.
Medical Research Council, Action Medical Research, Ferring Pharmaceuticals, GlaxoSmithKline.
MRC Centenary award
Examples of Physiology and Disease Mechanism:
1. McCloskey, C., Rada, C., Bailey, E., McCavera, S., van den Berg, H.A., Atia, J., Rand, D.A., Shmygol, A., Chan, Y.W., Quenby, S. and Brosens, J.J. et al, 2014. The inwardly rectifying K+ channel KIR7. 1 controls uterine excitability throughout pregnancy. EMBO molecular medicine, 6(9), pp.1161-1174. Doi: 10.15252/emmm.201403944
2. Lutton, E.J., Lammers, W.J., James, S., van den Berg, H.A. and Blanks, A.M., 2018. Identification of uterine pacemaker regions at the myometrial–placental interface in the rat. The Journal of physiology, 596(14), pp.2841-2852. Doi 10.1113/JP275688
3. Chan, Y.W., van den Berg, H.A., Moore, J.D., Quenby, S. and Blanks, A.M., 2014. Assessment of myometrial transcriptome changes associated with spontaneous human labour by high‐throughput RNA‐seq. Experimental physiology, 99(3), pp.510-524. Doi:10.1113/expphysiol.2013.072868
Example of Drug Discovery:
4. Wright, P.D., Kanumilli, S., Tickle, D., Cartland, J., Bouloc, N., Dale, T., Tresize, D.J., McCloskey, C., McCavera, S., Blanks, A.M. and Kettleborough, C., 2015. A high-throughput electrophysiology assay identifies inhibitors of the inwardly rectifying potassium channel Kir7. 1. Journal of biomolecular screening, 20(6), pp.739-747. Doi:10.1177/1087057115569156
Example of Computational Modelling:
5. Atia, J., McCloskey, C., Shmygol, A.S., Rand, D.A., van den Berg, H.A. and Blanks, A.M., 2016. Reconstruction of cell surface densities of ion pumps, exchangers, and channels from mRNA expression, conductance kinetics, whole-cell calcium, and current-clamp voltage recordings, with an application to human uterine smooth muscle cells. PLoS computational biology, 12(4), p.e1004828. https://doi.org/10.1371/journal.pcbi.1004828