The role of Reactive Sulfur Species in Ageing and Disease

Oxidative stress (OS) is a major driver of cellular dysfunction in ageing and disease. While Reactive Oxygen Species (ROS) have been solely linked to oxidative stress in the past, this project will investigate the roles of Reactive Sulfur Species (RSS), such as persulfides and polysulfides, as major contributors to cellular oxidative stress. This revolutionary idea will spark new discoveries into ageing and chronic disease aetiology and reveal novel molecular targets for advanced therapeutics.

Classic models of elevated OS will be utilised to study the role of RSS in OS-associated cellular effects:

• Ageing

Ageing and OS are intimately intertwined; OS increases cellular ageing, while aged cells have higher levels of OS. SOD1 knockout mice are a murine model of ageing, as these mice exhibit elevated OS and other hallmarks of ageing. While this has been assumed to be due to elevated ROS, my recent findings indicate that RSS are also elevated in this model of OS. Therefore, to model the ageing process, SOD1 KO will be compared to WT littermates. As we are interested in the ageing process, we are particularly interested in studying middle aged/pre-elderly subjects, to see if RSS play a role during ageing.

Circulating blood cells will be analysed via the following Aim methodologies at intervals to capture the entire ageing process. Additional tissues from middle-aged/pre-elderly mice (12-18 months) will be analysed. To examine if elevated RSS production alters the ageing process, an inducible CARS2 overexpressing WT and SOD1 KO mice will be generated and analysed as above, and RSS-donor compounds will be administered to WT and SOD1 KO mice.

• Motor Neuron Disease

Motor neurone diseases (MND) are conditions of elevated oxidative stress that result in motor neurone cell death. Amyotrophic Lateral Sclerosis (ALS) is the most common form of MND and SOD1 mutations are known drivers of inherited ALS, however, the biochemical or cellular mechanisms of this are not clear. My preliminary data shows that ALS-associated SOD1 mutants have decreased H2S metabolic capacity and elevated RSS, which points to H2S and/or RSS as potential culprits in ALS pathology.

• Tumour Biology

Tumours are associated with high levels of oxidative stress and hypoxia. Using cellular models and patient tumour explants, the role of RSS in driving hypoxic tumour progression will be studied at the chemical, molecular and cellular level.

Entry requirements

• Those who have a 1st or a 2.1 undergraduate degree in a relevant field are eligible.
• Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course.
• Those who have a 2.2 and an additional Masters degree in a relevant field may be eligible.
• Those who have a 2.2 and at least three years post-graduate experience in a relevant field may be eligible.
• Those with degrees abroad (perhaps as well as postgraduate experience) may be eligible if their qualifications are deemed equivalent to any of the above.
• University English language requirements apply.

To apply

Carefully read the application advice on our website below and submit your PhD application. 

https://le.ac.uk/study/research-degrees/research-subjects/molecular-and-cell-biology

Please forward enquiries to Dr Christopher Switzer by email on: cs876@leicester.ac.uk