Chemical biology tools for investigating the chemistry of cellular REDOX stress

Changes in the environment inside cells can be considered as alterations in cellular chemistry. The cellular environment can be thought to span a spectrum between reducing conditions (often characterised by a lack of oxygen, and the presence of chemicals that contain hydrogen) and oxidising conditions (often characterised by the presence of oxygen and reactive oxygen-containing species). The spectrum of REDucing to OXidising environment is known as REDOX chemistry. The REDOX environment in the cell results from external stimuli, and affects the function of the cell. Consequently, the REDOX environment can give rise to cellular changes that result in diseases. In this work, we propose that the reverse is also true - that the REDOX state of a cell at a given time will provide predictive information on the fate of a particular cell. Therefore, if it were possible to gain a global picture of the cellular REDOX state, this would be a revolutionary way of predicting cell fate, and hence treating disease. For this new technique to work we need a range of molecular tools that tell us about a given component of the REDOX state at any given time. The aim of our work is to develop and validate tools that detect the intracellular molecules that affect the cellular REDOX state, and provide imaging feedback on that state. By combing the feedback from several of these molecular tools we can infer information on the overall REDOX state. To achieve this aim we have assembled a team of people with the wide range of skills required to make the proposed molecular tools. Our team includes synthetic inorganic and organic chemists, people skilled in a range of imaging techniques, and biological scientists who will be able to apply the molecular tools that we will make. Only by combining the skills of everybody in our team will we be able to achieve the aims of this ambitious, but potentially revolutionary, programme of research.

Economic and societal impacts
The University of Oxford and King's College London will benefit from revenues generated by licences of IP arising from the proposed research, and from revenues generated by spin-out companies based on this work. 3-10 years.

Farmers, food producers and consumers will benefit from an increased understanding of REDOX stress in plants, which has the potential to improve food security and crop yield. REDOX stress in plants is particularly associated with flooding, which is becoming more prevalent due to climate change and has the greatest impact in developing countries. 5 years onwards.

Clinicians treating patients with REDOX-related diseases, and the patients themselves, will benefit from earlier and improved diagnosis. For example, for stroke patients, the tools might be used to determine the location and severity of the stroke in a timely manner. These advances will result in more effective treatment strategies being identified earlier, and consequently reduced costs to the NHS. In addition, the NHS will potentially benefit from shorter patient stays in hospital. 10-20 years.
The UK tax payer and Government will benefit from reduced costs for the NHS. The formation of a spin out company/ies will benefit both the local and national economy. The interaction of this company with global pharmaceutical companies will further benefit the national economy. 10-20 years.

Pharmaceutical companies are likely to be be significant beneficiaries of this work, and our industrial collaborators will provide guidance to ensure our work has maximum industrial relevance. One of the major goals of our future spin out companies will be to provide pharmaceutical companies with practically and economically viable options for patient stratification within clinical testing of new agents/combinations. The use of REDOX sensors could also potentially reposition cancer chemotherapies that have previously failed in clinical trials. 5-10 years.

Health care impact
Clinicians treating patients with diseases that involve REDOX stress, and the patients themselves (e.g. cancer, cardiovascular disease and stroke). Once established, our technology will provide a revolutionary method for the diagnosis of disease. Ultimately, we envisage that this technology will provide a signature for a given disease state. This signature will provide guidance on the type of drugs that should be used to treat the disease. Therefore, this methodology has the potential to expedite the process of selecting appropriate treatment for a disease. Specific examples of benefit to both clinicians and patients include: Tools that allow early diagnosis of diseases, which will include tools to undertake MRI and PET imaging in cardiovascular disease; New MR-based imaging methods for better evaluating key elements of the brain microenvironment that can influence therapeutic efficacy; The ability to map reactive oxygen species in many disease settings that are currently unstudied, will enable the development of new therapeutics and methods of treatment; Using the REDOX sensors as a companion diagnostic, we will be able to determine which drugs will be most effective for a given patient and perhaps avoid those likely to have the most detrimental side effects i.e. more personalised and therefore effective therapy. 10-20 years.

Public engagement
School children and the general public will benefit from 2-way engagement as well as learning opportunities giving a greater understanding of our work and science and medicine. We regularly engage with senior school age children therefore inspiring the uptake of STEM subjects pre-GCSE. Researchers on the Programme will benefit from training in and experience of communicating their work to school children and the general public. The Universities of Oxford and King's College London will benefit from the public engagement materials/activities that we will generate throughout the course of the Programme. 1-5 years.