Proteome wide identification of clinically-relevant carbon dioxide targets

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BackgroundScientific 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 processesResearch PlanHypercapnia 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