Davies Group - Protein Oxidation

Proteins are critical to all aspects of cell and tissue structure and function, but are prone to damage which can result in dysfunction and disease. Damage to proteins can arise from the reactions of radicals (reactive species with an unpaired electron) and other oxidants, which are generated in biological systems by both endogenous processes (e.g. metabolic pathways, inflammation and enzyme reactions) and also exposure to a wide range of external factors (UV and high-energy radiation, exposure to drugs, pollutants, mineral fibres, chemicals etc). Proteins are major targets due to their high abundance and their rapid rates of reaction with these oxidants. Damage to proteins can also arise from proteolytic enzymes that are activated by oxidants.

Oxidant-mediated damage has been linked to ageing, human disease, as well as changes in food quality and shelf life, agricultural yields and the quality and efficacy of medicines, vaccines and antibodies.

Current projects

1. Mapping protein changes in human carotid artery atherosclerotic plaques and blood samples by proteomics.

In this study we are examining whether there are significant changes in the complement of proteins present in human atherosclerotic plaques and whether this correlates (and predicts) the stability of these plaques. Rupture of such plaques is a major cause of strokes.

2. Novel blood biomarkers of cardiovascular disease

We are examining whether there are differences in the types and levels of materials released from atherosclerotic plaques into the circulation. Identification of these materials may provide novel biomarkers of cardiovascular disease and predict disease progression.

3. Oxidation- and glycation-induced modifications in human carotid artery atherosclerotic plaques.

Increased oxidation and elevated glucose levels are associated with the atherosclerosis. In this project we are identifying and quantifying protein modifications present in human tissue samples. Knowledge of the processes that give rise to damage, may guide new therapeutic strategies.

4. Proteomic analysis of proteins on percutaneous coronary intervention (PCI) angioplasty balloons to allow differentiation of subjects with stable versus unstable cardiovascular disease.

We have shown that PCI balloons used to open up blocked arteries retain proteins on their surface which can be identified and quantified by proteomics. This allows the interrogation of the biochemical processes occurring in individual plaques in humans, and opens the possibility of personalized medicine.

5. Proteolytic and oxidant-mediated modification of the extracellular matrix of the artery wall, and its role in atherosclerosis.

Recent data indicate that oxidants can activate (switch-on) the activity of powerful proteolytic enzymes that damage the structure of the artery wall. This project is examining how this occurs and which enzymes are the key players in extracellular matrix damage.

6. Myeloperoxidase, inflammation and cardiovascular disease.

Activated leukocytes which accumulate at sites of inflammation, including within the artery wall, release the heme enzyme myeloperoxidase. Elevated levels of this enzyme and the species that it generates are strongly associated with tissue damage. We are examining how this enzyme damages the cells and extracellular matrix of arteries.

7. Protection against myeloperoxidase-mediated damage by small anions and enzyme inhibitors

Inhibition of myeloperoxidase, or provision of alternative substrates, may modulate the damage induced by this enzyme within the inflamed artery wall. We have shown that a number of small anions can alter the extent of damage, at concentrations that can be readily achieved in humans.

8. Kinetics and mechanisms of oxidative damage to proteins induced by hypochlorous acid, peroxynitrous acid, singlet oxygen, electrophiles, peroxides, sugars and metal ions.

Understanding how oxidants react and target proteins, and individual sites within these, is critical to understanding biological damage and the development of protective strategies.

9. Novel selenium- and sulfur-based antioxidants

A number of enzymes have selenium and sulfur atoms in their active sites which make these highly efficient protective agents against damage. This project aims to develop low molecular mass analogues to protect against, or modulate disease.

10. Role of molecular crowding in modulating protein structure, function and oxidation

Tissues and cells are highly crowded environments, but many model systems use simple dilute systems to model these complex systems. Our data indicate that the high concentrations of (macro)molecules in cells and biological fluids have profound effects on protein structure and function, cellular signaling, oxidation reactions and aggregation. Understanding these effects is critical to understanding cellular biochemistry.

11. Detection, characterization and quantification of protein cross-links

Many human diseases including cardiovascular and neurodegenerative conditions (e.g. Alzheimer’s and Parkinson’s diseases) are characterized by the accumulation of large protein aggregates. The nature of these species and the cross-links between proteins that drive aggregate formation are poorly understood. We are developing new approaches to detect and identify these species, and are examining aggregate formation in cells, tissues, food samples and medicines.

Please contact Michael Davies, davies@sund.ku.dk, if you are interested in any of these projects, or other opportunities.

The Protein Oxidation Group has received, and continues to be funded by, grants from a number of private and public foundations including: Novo Nordisk Fonden (Laureate Grants x 2 and Project grants), Lundbeck Fonden, Danish Council for Independent Research, La Caixa Foundation, Augustinus Foundation, AP Møller Foundation, Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis' Legat.