Investigating the role of Aquaporins in age related diseases

Description

Physical frailty, with its associated immobility and disability, is a major factor limiting independence among older people. A key contributor to frailty is a decline in muscle mass and strength (sarcopenia) and the burden of sarcopenia is substantial, with a cost to the NHS of ~£2.5bn/pa. There remains a clear need to identify and test new strategies to reduce the incidence, and consequences, of sarcopenia but the underlying mechanisms remain poorly understood. Not only that but elderly individuals experience a range of musculoskeletal issues, including muscle weakness, joint degeneration, and back problems, as well as other age-related health conditions such as OA, all of which can contribute to chronic pain.

Disruption of the neuromuscular junction (NMJ), loss of motor units and a decreased number of muscle fibres is characteristic of sarcopenia. Despite strong associations between the losses of muscle fibres and motor axons, a cause–effect relationship has not been established. My work identified that elevated levels of Hydrogen Peroxide (H2O2), a key Reactive Oxygen Species (ROS) is key to this process and this PhD study will examine this using an integrated cellular approach.

It is proposed that the major route of passage of H2O2 across cell membranes is by channels called "Aquaporins" (AQPs). Despite the detrimental effects of H2O2 on muscle and the work showing AQP involvement in the control of the H2O2 gradients, there are only sparse reports of AQPs in NMJ-associated cells and no studies examining H2O2 transport or the effect of ageing. Similarly, the role of ROS, including H2O2, in pain signalling and chronic pain conditions is an area of growing interest.

Several studies have suggested that oxidative stress and the production of ROS, may play a role in the pathogenesis of neuropathic pain. However, the specific mechanisms and the extent of hydrogen peroxide signalling in chronic neuropathic pain are not fully elucidated.
We hypothesise that AQPs are the primary means of regulating H2O2 movement and that dysregulation of this transport is key to the aberrant production of H2O2 resulting in oxidative stress and leading to the development of several age-related conditions including sarcopenia and chronic neuropathic pain.

This PhD will provide an ideal opportunity for an individual with an interest in physiology, redox signalling, neurological and neuromuscular diseases. A range of research methods will be used throughout the project such as in vivo and in vitro methodologies, confocal imaging, FACS, RNAseq and beyond.