Preterm labour prevention: composition and characterisation of the predominate KV7 channel subunits in human uterine tissue and smooth muscle cells

Despite spontaneous preterm birth being a major contributor to perinatal morbidity and mortality worldwide, it cannot be accurately predicted or prevented or treated. Our research into the control of uterine contractility has led us to propose potassium channels encoded by KCNQ2-5 genes (KV7 channels) as a potential drug target to inhibit preterm uterine contractions and potentially immune cell activation. Only specific KCNQ1-5 and accessory KCNE1-5 are functionally expressed in pregnant human uterine tissue (myometrium) from women at term and in labour. Pharmacological activation of Kv7 channels inhibit pregnant human and mouse myometrium contractions in vitro, with ML213 (a KV7.4/ KV7.4, KV7.2and Kv7.5 preferential activator) being the most effective. Kv7 channel activators delay preterm birth in an experimental model. This provides essential 'proof of principle' data for functional KV7 channels in human myometrium and highlights the potential of KV7 channel activators to inhibit uterine contractions and preterm delivery. The aim of this PhD project is to determine the specific architecture of the human uterine KV7 channel and its interactions with KCNE proteins as well as aspects of KV7.4 channel regulation and trafficking in human myometrium tissue and cells. A secondary aim is to determine uterine cell type differences in Kv7 expression in order to understand potential pharmacological impact (e.g. immune cells). A variety of imaging and molecular techniques will be used including using super resolution confocal imaging, multiphoton microscopy, structural illumination imaging, gene knockdown and overexpression, and RNAseq.

The project has flexibility to focus more on protein structure, cellular regulation and gen e manipulation or membrane biophysics approaches depending on candidate interest/skill set.

Training will be provided in both supervisors' well-equipped research facilities/laboratories. The student will have access to KCL core and BRC facilities (e.g. Nikon Imaging Centre and BRC Flow cytometry and genomics platforms), relevant personal development training, and journal clubs and seminars.