Proteome wide identification of clinically-relevant carbon dioxide targets

Background

Scientific consensus has considered CO2, at best, a relatively inert metabolic by-product, and at worst, a toxic molecule with severe clinical consequences if dysregulated. However, clinical observations demonstrate elevated PCO2 might be beneficial to patients in certain circumstances.

There is clinical value in addressing the molecular mechanisms for the physiological effects of CO2. A large cohort study (LUNG SAFE, NCT02010073) and retrospective analysis of the Acute Respiratory Distress Syndrome Network demonstrated the potential therapeutic benefit of elevated PCO2. However, elevated PCO2 can also have harmful pathophysiological effects on the lung (alveolar fluid clearance and epithelial cell repair), skeletal muscle and innate immunity and host defence.

Understanding the therapeutic potential for CO2 requires knowledge of its sensors. We have established two methodologies for identifying CO2 target proteins, experimental and computational.

We have deployed the experimental methodology to identify CO2-binding proteins and investigate the therapeutic potential for CO2. We have identified histones as a CO2 target and demonstrated that CO2 modifies lysine targeted for acetylation/methylation in transcriptional control. This studentship will

1. Investigate the biomedical consequences for histone modification by CO2 to reveal the therapeutic potential for PCO2 in the clinic.
2. Deploy computation to reveal further CO2 targets in the human proteome that might impact on these processes

Research Plan

Hypercapnia is known to target the Wnt signalling pathway and Wnt dysregulation is linked to a range of diseases including cancer and cardiovascular disease.

The research plan is split an experimental stream (four years) and a computational stream (one year).

The experimental stream will address the hypothesis that hypercapnia impacts Wnt signalling through modifying histone targets thus altering the production of Wnt-target gene products.

The computational stream will use a computational approach to identify all CO2 binding sites in the human proteome with an emphasis on targets in the Wnt signalling pathway.

The first examines histone CO2-binding in vitro; the second examines histone CO2-binding

The CDT has five primary beneficiaries:
The CDT cohort
Our students will receive an innovative training experience making them highly employable and equipping them with the necessary knowledge and skillset in science and enterprise to become future innovators and leaders. The potential for careers in the field is substantial and students graduating from the CDT will be sought after by employers. The Life Sciences Industrial strategy states that nearly half of businesses cite a shortage of graduates as an issue in their ability to recruit talent. Collectively, the industrial partners directly involved in the co-creation of the proposal have identified recruitment needs over the next decade that already significantly exceed the output of the CDT cohort.
Life science industries
The cohort will make a vital contribution to the UK life sciences industry, filling the skills gap in this vital part of the economy and providing a talented workforce, able to instantly focus on industry relevant challenges. Through co-creation, industrial partners have shaped the training of future employees. Additional experience in management and entrepreneurship, as well as peer-to-peer activities and the beginning of a professional network provided by the cohort programme will enable graduates to become future leaders. Through direct involvement in the CDT and an ongoing programme of dissemination, stakeholders will benefit from the research and continue to contribute to its evolution. Instrument manufacturers will gain new applications for their technologies, pharmaceutical and biotech companies will gain new opportunities for drug discovery projects through new insight into disease and new methods and techniques.
Health and Society
Research outputs will ultimately benefit healthcare providers and patients in relevant areas, such as cancer, ageing and infection. Pathways to such impact are provided by involvement of industrial partners specialising in translational research and enabling networks such as the Northern Health Science Alliance, the First for Pharma group and the NHS, who will all be partners. Moreover, graduates of the CDT will provide future healthcare solutions throughout their careers in pharmaceuticals, biotechnology, contract research industries and academia.
UK economy
The cohort will contribute to growth in the life sciences industry, providing innovations that will be the vehicle for economic growth. Nationally, the Life Sciences Industrial Strategy Health Advanced Research Programme seeks to create two entirely new industries in the field over the next ten years. Regionally, medicines research is a central tenet of the Northern Powerhouse Strategy. The CDT will create new opportunities for the local life sciences sector, Inspiration for these new industries will come from researchers with an insight into both molecular and life sciences as evidenced by notable successes in the recent past. For example, the advent of Antibody Drug Conjugates and Proteolysis Targeting Chimeras arose from interdisciplinary research in this area, predominantly in the USA and have led to significant wealth and job creation. Providing a cohort of insightful, innovative and entrepreneurial scientists will help to ensure the UK remains at the forefront of future developments, in line with the aim of the Industrial Strategy of building a country confident, outward looking and fit for the future.
Institutions
Both host institutions will benefit hugely from hosting the CDT. The enhancement to the research culture provided by the presence of a diverse and international cohort of talented students will be beneficial to all researchers allied to the theme areas of the programme, who will also benefit from attending many of the scientific and networking events. The programme will further strengthen the existing scientific and cultural links between Newcastle and Durham and will provide a vehicle for new collaborative research.