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Leaders: Associate Professor Andrew Murphy and Professor Merlin Thomas

Obesity and diabetes are the leading cause of premature death and illness, and is largest threat to public health in our country. People suffering from obesity and diabetes largely die of cardiovascular disease (CVD). Adding to this is the fact that atherosclerotic lesion regression (reversal of disease) is impaired in obesity/type 2 diabetes (T2D) when cholesterol levels are optimally controlled. This suggests factors other than lipids affect the ability of a lesion to regress in these patients, which is a problem that is vital to address.

Over the past few years we and others have shown an important role for the abundance of blood monocytes to the progression and impaired regression of atherosclerotic lesions. We have discovered that the pathways contributing to monocyte production in obesity and diabetes differ significantly, showing how distinctive these diseases are. However, we did discover that one of the initiating ligands of monocyte production in both diseases is S100A8/A9. In diabetes S100A8/A9 production is driven by hyperglycaemia in neutrophils, while in obesity S100A8/A9 is produced by adipose tissue macrophages. It appears that in both models excess nutrients drive metabolic pathways (i.e. glycolysis or beta-oxidation) which can trigger off-shoot pathways to produce reactive dicarbonyls. We hypothesise that these metabolites could trigger S100A8/A9 expression.

We have acquired a novel S100A8/A9 blocking drug (Paquinimod; ABR-215757) that is currently an orphan drug for systemic sclerosis. We will evaluate this drug in models of uncontrolled and controlled diabetes and obesity to determine if this can prevent monocyte production. Finally, we will test this drug in atherosclerosis experiments to determine if blocking S100A8/A9 can prevent the accelerated atherosclerosis seen with these metabolic diseases.

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