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:
The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy.
McCloskey C, Rada C, Bailey E, McCavera S, van den Berg HA, Atia J, Rand DA, Shmygol A, Chan YW, Quenby S, Brosens JJ, Vatish M, Zhang J, Denton JS, Taggart MJ, Kettleborough C, Tickle D, Jerman J, Wright P, Dale T, Kanumilli S, Trezise DJ, Thornton S, Brown P, Catalano R, Lin N, England SK, Blanks AM.
EMBO Mol Med. 2014 Jul 23;6(9):1161-74. doi: 10.15252/emmm.201403944
Assessment of myometrial transcriptome changes associated with spontaneous human labour by high-throughput RNA-seq.
Chan YW, van den Berg HA, Moore JD, Quenby S, Blanks AM.
Exp Physiol. 2014 Mar;99(3):510-24. doi: 10.1113/expphysiol.2013.072868. Epub 2013 Nov 22.
Example of Drug discovery:
A High-Throughput Electrophysiology Assay Identifies Inhibitors of the Inwardly Rectifying Potassium Channel Kir7.1.
Wright PD, Kanumilli S, Tickle D, Cartland J, Bouloc N, Dale T, Tresize DJ, McCloskey C, McCavera S, Blanks AM, Kettleborough C, Jerman JC.
J Biomol Screen. 2015 Jul;20(6):739-47. doi: 10.1177/1087057115569156. Epub 2015 Feb 5.
Example of Computational Modelling:
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.
Atia A, McCloskey C, Shmygol A, Rand DA, Van den Berg H, Blanks AM.
PLOS Computational Biology in press