The role of the skeletal muscle ryanodine (RYR1) receptor in uterine vascular and smooth muscle function

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are the most common cause of non-dystrophic neuromuscular disorders in humans, including early-onset myopathies, (exertional) rhabdomyolysis (ERM) and malignant hyperthermia (MH), a potentially life-threatening anaesthesia complication in response to volatile anaesthetics and depolarizing muscle relaxants. RYR1 encodes the skeletal muscle ryanodine receptor (RYR1), the principal sarcoplasmic reticulum (SR) calcium release channel with a crucial role in excitation- contraction coupling (ECC), and muscle contraction. RYR1 mutations implicated in ERM and MH are almost always gain-of-function mutations associated with massive increases in calcium release, whereas recessive and dominant RYR1 mutations leading to a reduction of the available SR calcium pool have been associated with various myopathies and muscle weakness. Considering its almost ubiquitous expression, RYR1-mediated calcium release is likely to play important signalling roles in tissues and organs other than skeletal muscle, however, such roles have only been partially explored to date.

We have recently identified a novel human bleeding phenotype associated with dominant RYR1 gain-of-function mutations, characterized by profound menorrhagia/post-partum haemorrhage in mutated females. Investigating a mouse model of RYR1-related MH/ER, the RYR1 Y522S mouse, we have confirmed an increased bleeding tendency due to impaired vascular smooth muscle cell (SMC) contractility. The precise cause of the prominent obstetric and gynaecological manifestations in RYR1-mutated states remains currently uncertain, but is likely to involve reduced contractility of uterine blood vessels and SMCs.

Utilising the RYR1 Y522S mouse model, we will determine how the RYR1 mutation affects uterine SMC function in non-pregnant and pregnant tissues. We hypothesize that the mutation causes an SR calcium leak resulting in raised intracellular calcium, altered uterine contractility, increased SR and plasma membrane Ca ATPase and generation of excess reactive oxidative species; we would anticipate that the uterine vasculature (and vessels in the endometrium or placenta/decidua) would be similarly affected. The PhD project will therefore focus on characterising the impact of the RYR1 mutation on uterine myometrium and blood vessel contractility in vitro using pharmacological RyR and calcium modulators. Intracellular calcium signalling events will be investigated using digital fluorescent and confocal imaging. Timing of birth/length of labour will be studied in vivo.

The ultimate goal of this project is to further clarify the role of the RYR1 receptor in uterine contractility and pathological conditions where this is impaired. This project also has scope to develop clinically.

The successful candidate for this project will be registered in, and be part of the vibrant postgraduate research community in, the King’s College London School of Life Course Sciences (https://www.kcl.ac.uk/lsm/schools/life-course-sciences/index.aspx), in the Faculty of Life Sciences and Medicine (https://www.kcl.ac.uk/lsm/index.aspx).

Your Profile
Applications are invited from candidates with an interest in multi-disciplinary research and training in women’s and children’s health, and have a 1st class or upper second degree in a relevant bioscience, biomedical science, physical science or health related discipline. A master’s degree in a relevant area will be an advantage, but not essential.

Application
Application for this studentship is via King's Apply, where you should apply to the King’s Health Partners Institute of Women and Children’s Health Programme and select Project 3.
King's Apply: https://apply.kcl.ac.uk/